James M. Ntambi
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Margrit Schwarz
Sep 1, 1998; 39:1833-1843
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Jennifer L. Macdonald
May 1, 2005; 46:1061-1067
Methods

MS Brown
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W Gamble
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Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews

Mohamad Navab
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Mohamad Navab
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JL Dixon
Feb 1, 1993; 34:167-179
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EJ Blanchette-Mackie
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Linda J. Pike
Jul 1, 2006; 47:1597-1598
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JF Oram
Dec 1, 1996; 37:2473-2491
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DL Brasaemle
Nov 1, 1997; 38:2249-2263
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K Schoonjans
May 1, 1996; 37:907-925
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The Committee to Protect Journalists named winner of the Chatham House Prize 2018 News Release sysadmin 5 October 2018

The Committee to Protect Journalists (CPJ) has been voted the winner of this year’s Chatham House Prize.

Chatham House awarded major centenary grant to establish Stavros Niarchos Foundation Wing News Release sysadmin 16 April 2019

Chatham House has been awarded a transformational £10m grant ahead of its upcoming 2020 centenary.

Creon Butler appointed to lead Global Economy and Finance Programme News Release sysadmin 22 October 2019

Creon Butler has been appointed to lead the Global Economy and Finance programme at Chatham House, joining the institute at the beginning of December. He will also form part of the institute’s senior leadership team.

Sir David Attenborough and the BBC Studios Natural History Unit awarded Chatham House Prize 2019 for ocean advocacy News Release sysadmin 18 November 2019

The 2019 Chatham House Prize is awarded to Sir David Attenborough and Julian Hector, head of BBC Studios Natural History Unit, for the galvanizing impact of the Blue Planet II series on tackling ocean plastic pollution.

The regional and international implications of restrictions to online freedom of expression in Asia 25 March 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 12 March 2021 Online

Panellists discuss the latest developments affecting online freedom of expression in the Asia region.

Please note this is an online event. Please register using the link below to finalize your registration.

In recent years, state-led clampdowns on online freedom of expression have become widespread in several countries across Asia, further intensified by the COVID-19 crisis.

The reasons for this are complex and diverse – drawing upon history, culture and politics, in addition to external influences. Across the region, governments have been accused of silencing online criticism and failing to uphold rights to free speech.

Individuals have been arrested, fined or attacked for the alleged spread of ‘fake news’, raising concern among human rights organizations. In some countries, this has culminated in the imposition of new social media rules, which could require social media companies to censor posts and share decrypted messages.

In China, the government’s restrictive online regime has relied on a combination of legal, technical and manipulation tactics to manage control of the internet, and now includes attempts at censorship beyond its borders.

Panellists will discuss the latest regional developments affecting online freedom of expression in the Asia region, and will consider the broader regional and international implications for technology governance.

This webinar launches the publication Restrictions on online freedom of expression in China: The domestic, regional and international implications of China’s policies and practices.

Battle lines being drawn over online freedoms in Asia Expert comment NCapeling 22 March 2021

Social media giants are increasingly clashing with Asian governments over free expression and censorship as the region lurches towards digital authoritarianism.

Freedom of expression was subject to significant restrictions in Asia even before the pandemic, with several governments having enacted laws that stifle online debate. But since COVID-19, restrictions have increased even further due to a rash of so-called ‘emergency measures’ introduced by governments across the region.

Bangladesh, India, Indonesia, Malaysia, Myanmar, Nepal, Pakistan, the Philippines, Sri Lanka, Thailand, and Vietnam have all put new laws into place, and many restrictions are already being applied in a draconian fashion, such as in the Philippines and Bangladesh.

As outlined in a new Chatham House research paper, one inspiration behind this trend is China, home to the world’s most sophisticated and restrictive system of internet control. The Chinese government’s restrictive online regime, which has tightened further under COVID-19, relies on a combination of legal regulations, technical controls, and proactive manipulation of online debates.

This model was an inspiration for Vietnam’s cybersecurity law, as well as Myanmar’s new draft cybersecurity bill, proposed by the Military-run State Administration Council in the wake of the military coup last month, which would give the military there extensive powers to access individuals’ data, restrict, or suspend access to the internet.

This ‘sovereignty and control’ model of internet governance is also gaining impetus through China’s ‘Digital Silk Road’ initiative, under which the Chinese government is exporting both its technology – such as through the establishment of smart cities, the installation of AI, and surveillance technology – and its vision of how the internet should be governed.

In November 2020, Xi Jinping pledged to further deepen cooperation with ASEAN through the Digital Silk Road, and the pandemic has expanded the appeal of Chinese surveillance technologies and data collection platforms to governments both in Asia and beyond. China’s Health Silk Road, which aims to promote global health cooperation, is centered on the Chinese government’s high-tech model under which civic freedoms are sacrificed in the name of public health.

An alternative model

This ‘sovereignty and control’ model is increasingly at odds with the more ‘human-centric’ model of tech governance favoured by many democratic states, Western social media companies, and international institutions, especially the United Nations (UN) and European Union (EU).

Although this emerging model also involves regulation, it is regulation which aims to be inclusive, risk-based, and proportionate – balancing the need for protection against online harms with the need to preserve freedom of expression. It is a multi-stakeholder, rights-based approach which brings together not just governments but also representatives of the private sector, civil society, and academia. The EU’s draft Digital Services Act and the UK’s proposals for an Online Safety Bill are both reflective of this approach.

Western social media giants such as Facebook and Twitter have recently introduced new policies which seek to identify and mitigate online harms, such as hate speech and disinformation. Industry bodies such as the Global Network Initiative, independent oversight bodies such as the Oversight Board established by Facebook, and civil society advocacy and initiatives such as the Santa Clara Principles on Transparency and Accountability in Content Moderation are also an important part of the picture.

Admittedly, these various digital governance initiatives are in some cases embryonic, and are by no means a silver bullet solution to the complex problem of online content moderation, which continues to be hotly debated in democratic societies. But they are at least underpinned by the same philosophy – that international human rights law standards must continue to apply even during emergencies such as COVID-19. With the Biden administration in the US prioritizing tech governance in its policy agenda, there is added momentum to the international leadership behind this model.

A clash of ideology

These conflicting philosophies are playing out in debates on technology governance at the UN, with one group of countries led by China and Russia advocating for greater government control of the internet, and many Western democracies emphasizing the need for an open, global internet that protects human rights.

These differing ideologies are also creating tensions between Western social media companies operating in Asia and the various governments in that region which have increased restrictions on online expression. And the gulf between the two appears to be widening.

In 2017, the Thailand government threatened Facebook with legal action unless it agreed to remove content critical of Thailand’s royal family and, in 2020, Facebook announced it had been ‘forced to block’ such material. Also in 2020, the Vietnam government pressured state-owned telecom companies to throttle internet traffic to Facebook, effectively restricting access to the platform, until Facebook agreed to take down content the government deemed to be anti-state.

Platforms refuse to silence legitimate criticism

However, Silicon Valley’s social media companies have also been pushing back. Facebook restricted the accounts of Myanmar’s military on the basis of ‘spreading misinformation’ in the wake of the military’s imposition of an internet shutdown that blocked access to Facebook, Twitter, and Instagram. And Twitter resisted requests by the Indian government to block accounts involved in protests by farmers.

Twitter stated that while it would block any accounts which it felt incited violence, it would not take action on accounts belonging to news media entities, journalists, activists, and politicians because it believed that would ‘violate the fundamental right to free expression under the Indian law’. The Indian government responded by fast-tracking stringent new social media regulations heavily criticized by rights groups for increasing government power over content on social media platforms, including online news.

So how can social media companies find avenues for operating in Asia and beyond without being co-opted into the lurch towards digital authoritarianism? There are no easy answers here, but collaboration is key. Cooperation between tech companies and local civil society partners can help companies better understand risks to human rights in the country concerned and how they might be mitigated. And tech companies are more effective in alliance with each other than acting on their own, such as the refusal by Facebook, Google, Telegram, and Twitter to hand over data on protestors to the Hong Kong police.

The fact that in many countries in Asia there are no alternatives to Western social media companies – unlike China, where platforms such as WeChat are part of the government’s internet control apparatus – gives the companies concerned some leverage. In February 2020, Facebook, Google, and Twitter together – through the Asia Internet Coalition – threatened to leave Pakistan in response to the government’s draconian proposals to regulate social media. Along with pressure and lawsuits from civil society, this forced the government into retreat, although the tussle over the new rules, introduced in November, continues.

At a time when illiberalism was already on the rise in Asia (including in democracies – Freedom House has just downgraded India’s status from ‘free’ to ‘partly free’), COVID-19 has made tighter state control of online freedom of expression even more attractive to many governments. As it seems increasingly unlikely that restrictions enacted under the guise of pandemic-related emergency measures will be repealed once the COVID-19 crisis ends, it is even more important that tech companies work with civil society on the ground to minimize the censorship of citizen voices.

Monitoring of trade deals needs a risk-based approach Expert comment NCapeling 24 May 2021

On human rights issues, trading partners must do more than trust to luck.

The recent row within the UK government about the treatment of agricultural products in a proposed new trade deal with Australia provides a reminder that changes to trading arrangements can have social and environmental costs, as well as benefits.

Although the UK government clearly feels political pressure to demonstrate its ‘Global Britain’ credentials with some speedily concluded new deals, rushing ahead without a full understanding of the social, environmental, and human rights implications risks storing up problems for later. In the meantime, calls for better evaluation and monitoring of trade agreements against sustainability-related commitments and goals – ideally with statutory backing – will only get stronger.

EU experiences with these kinds of processes are instructive. For more than 20 years the Directorate General for Trade of the European Commission (DG Trade) has been commissioning sustainability impact assessments (SIAs) from independent consultants in support of trade negotiations, and since 2012 these assessments have explicitly encompassed human rights impacts as a core part of the analysis.

These processes have since been augmented with a programme of periodic ‘ex post’ evaluations of trade agreements to ‘analyse the observed economic, social, human rights, and environmental impacts’ of live trade deals and to make recommendations about any mitigation action which may be needed.

For credibility and objectivity, the Commission outsources much of its sustainability assessment and ex post evaluation activities to independent consultants, who are encouraged to innovate and tailor their approaches subject to broad methodological parameters laid down by the Commission. Over time, experiences with specific assessment and monitoring assignments have enabled external SIA practitioners – and the Commission itself – to progressively strengthen these processes and underlying methodologies.

Yet despite the improvements there remains legitimate questions about whether the human rights aspects of these SIA processes – and subsequent evaluations – are having real policy impact. The difficulty of predicting human rights impacts of trade agreements in advance – as the COVID-19 crisis amply demonstrates – suggests a need for realism about the extent to which a ‘one off’ process, often carried out at a time when there is only ‘agreement in principle’ as to future trading terms, can produce a robust roadmap for heading off future human rights-related risks.

Human rights impact assessments have a potentially valuable role to play in laying down the substantive and structural foundations for future human rights monitoring as part of a broader, iterative, human rights risk management strategy. But the fragmented manner in which many trade agreements approach human rights issues, and the fact that outcomes are the product of negotiation rather than necessarily design, make it difficult to turn this vision into reality.

Controversies surrounding the SIA process for the EU-Mercosur agreement illustrate why striving for more coherence in the identification and subsequent management of human rights-related risks is important. In June 2019, the Commission decided to wrap up negotiations with the South America Mercosur bloc, even though the SIA process for the proposed agreement was still incomplete and the interim and final SIA reports yet to be delivered. Frustrated NGOs made their feelings clear in the form of a formal complaint – and a slap on the wrist from the EU Ombudsman duly followed.

However, when it eventually appeared in December 2020, the final SIA report for the EU-Mercosur deal did include a number of interesting recommendations for responding to specific areas of human rights-related risk identified through the pre-signing assessment process – such as flanking measures designed to address issues pertaining to health, equality, and protection of indigenous peoples, and stressing the need for ‘continuous monitoring’.

Hopefully these recommendations will be proactively followed up, but there are reasons not to be overly optimistic about that. To the extent that these recommendations might have required, or benefitted from, some tweaks to the terms of the trade agreement itself, it was clearly too late. And while there may be opportunities for EU institutions to follow up the recommendations through unilateral ex post evaluation processes, current legal, policy, and institutional arrangements provide few guarantees this will take place.

The credibility of the EU SIA programme has clearly taken a knock because of the problems with the EU-Mercosur process, and stakeholders could be forgiven for questioning whether expending time and effort on engaging in these processes is actually worthwhile. As a first step towards rectifying this, the Commission should be transparent about how it plans to respond to the EU-Mercosur SIA recommendations regarding flanking measures and follow up – ideally consulting with stakeholders about the various human rights monitoring options available.

Looking further ahead, the Commission should be urging SIA practitioners to deal more expansively with the options for follow up human rights monitoring in future SIA reports, setting out recommendations not just on the need for ongoing monitoring of human rights-related issues but on the detail of how this might be done, and how progress towards human rights-related goals could be tracked. And creativity should be encouraged because, as detailed in a newly-published Chatham House research paper, there may be more opportunities for human rights monitoring than first appear.

The SIA process could also provide a forum for exploring complementary measures needed to make future monitoring efforts as effective as possible – jointly and unilaterally; politically, structurally, and resources-wise; both within the framework of the trading relationship and extraneously. The credibility of the process – and hence stakeholder trust – would be further enhanced by commitments from the Commission to be more transparent in future about how different human rights monitoring recommendations laid out in SIAs have been taken into account in subsequent negotiations, in the supervisory arrangements developed for specific trading relationships, and in the implementation of EU trade policy more generally.

The trickle-up effect of rights-based climate litigation Expert comment NCapeling 16 November 2021

With governments failing in their pledges and companies accused of ‘green-washing’, human rights-based litigation is increasingly important for accountability.

Tuvalu’s foreign minister addressing COP26 while standing knee-deep in seawater was a stark illustration of how the climate emergency directly and imminently threatens the most basic human rights protected under international law – including to the right to life, self-determination and cultural rights.

Human rights are now a fundamental component of more than 90 per cent of the climate litigation currently taking place outside the US, highlighting the international reach of human rights law and how its emphasis on protecting the most vulnerable helps diverse communities find common arguments for shared goals.

Cases are set to continue and to evolve but three types of claim are emerging, each of which is examined in a new Chatham House briefing paper.

1. Enforcing commitments

One category of cases seeks to hold states accountable for pledges they have made on climate change, such as emission reduction targets made under the framework of the 2015 Paris Agreement. Drawing on human rights obligations, governments can be charged with not taking sufficient steps to implement these pledges.

The case of Leghari v Pakistan (2015) concerned the government’s failure to carry out the National Climate Change Policy of 2012 and the Framework for Implementation of Climate Change Policy (2014-2030). The Lahore High Court held that several of the human rights enshrined in Pakistan’s constitution cover climate change and ‘provide the necessary judicial toolkit to address the government’s response to climate change’.

The court ordered the government to carry out measures such as publishing an adaptation action plan realizable within a few months of the order and establishing a Climate Change Commission to monitor progress.

2. Positive duties to mitigate risks

Many rights-based climate cases are being brought to clarify the scope of states’ positive duties under human rights law to take meaningful steps to protect their citizens against foreseeable risks to life and other rights.

This ‘trickle-up’ effect of human rights was prominent in the case of State of the Netherlands vs the Urgenda Foundation (2019) where the Dutch Supreme Court held that reducing emissions with the highest possible level of ambition amounts to a ‘due diligence standard’ for states to comply with their positive duties to adopt adequate measures to address climate change. Human rights law was also used by the court to fill in the content of the due diligence standards.

There is also a growing trend for rights-based actions to be brought against corporations, such as a recent case which drew on the UN Guiding Principles on Business and Human Rights to define the parameters of Shell’s duty of care and due diligence obligations in relation to carbon emissions under Dutch law. The court ordered Shell to reduce emissions by a net rate of 45 per cent by the end of 2030 – relative to 2019 figures – through its group corporate policy.

3. Avoiding harm in climate action

The global human rights regime is also increasingly invoked in litigation concerning states’ negative obligations to ensure that their climate mitigation and adaptation activities do not themselves contribute to human rights violations (including discrimination) and that states prioritize adaptation measures for those most at risk in a just and equitable way.

As Chatham House’s paper makes clear, this kind of litigation ‘puts pressure on governments to expand their approach to tackling climate change beyond purely a regulatory one to a more holistic strategy’.

Closing the climate justice gap

Climate and environmental litigation grounded in human rights is set to continue given the overwhelming scientific evidence of risks associated with human-induced climate change and the limited confidence in pledges made by states and corporations alike – including those made recently at COP26.

A growing collaboration between civil society organizations and vulnerable communities in relation to both the protection of nature and the enjoyment of their land and cultural rights was evident at COP26, and this alliance will add further momentum to the trend for rights-based climate litigation based on the rights of indigenous and other vulnerable communities, especially on issues such as deforestation.

But more challenges are coming. International human rights law recognizes a duty of international cooperation but there remain significant hurdles for climate-vulnerable communities in developing countries to compel action by richer nations despite the vast debts of ‘carbon colonialism.’

One big issue is the problem of extraterritoriality, as the extent to which states owe obligations to individuals outside their territory is contested. Courts in both Germany and the Netherlands have rejected claimants from developing countries in domestic class actions on this basis. But a recent decision of the UN Committee on the Rights of the Child on a complaint brought by Greta Thunberg and other youth activists against five countries opens the door for further litigation.

One of a number of cases being brought by youth claimants across the world, the committee concluded that a state’s human rights duties can – in some instances – extend to children in other countries. This includes any activities on the territory that host states have the power to prevent from causing ‘transboundary harm’ – such as emissions from the territory – where these activities ‘significantly’ impact the enjoyment of human rights of persons outside the territory.

To date, high-profile rights-based cases have argued for policy change and stronger targets underpinned by binding legislation responsive to the science. Claims are set to become more complex and contested. Building on scientific developments in climate attribution, rights-based litigation is now tackling other difficult questions such as apportioning responsibility and remedial action.

These cases examine both historically high emitters and the public and private actors who either continue specific activities or refrains from action in the face of the overwhelming science linking human activities such as extraction and burning of fossil fuels to deforestation and climatic consequences.

Courts are also likely to explore the duties that states and corporations owe to deliver a ‘just transition’ away from carbon-intensive industries, given the benefits of growth and climate action are already unevenly distributed.

A holistic human-rights based approach

Several states together with civil society are leading the charge for global recognition of the right to a healthy, clean, and sustainable environment in the United Nations (UN) Human Rights Council, and multi-stakeholder processes are defining what effective corporate due diligence looks like.

In addition, UN-appointed special rapporteurs are delivering practical guidance on how to devise solutions which are fair, non-discriminatory, participatory, and climate-resilient without exacerbating inequality – including difficult issues of planned relocation – and UN Human Rights Treaty Bodies are unpacking the duty of international cooperation to act in good faith to address loss and damage.

Recently the Committee on the Elimination of Discrimination Against Women recommended the Marshall Islands, in order to meet its duty to its citizens, should actively seek international cooperation and assistance – including climate change financing – from other countries but in particular the US, whose ‘extraterritorial nuclear testing activities have exacerbated the adverse effects of climate change and natural disasters’ in the islands.

Elizabeth Wilmshurst CMG appointed Honorary Queen’s Counsel News release jon.wallace 14 January 2022

Founder of the International Law Programme at Chatham House recognized for her major contribution to the law of England and Wales.

Elizabeth Wilmshurst CMG, distinguished fellow of Chatham House’s International Law Programme, has been awarded the title of Honorary Queen’s Counsel (QC Honoris Causa), recognizing her major contribution to the law of England and Wales, outside practice in the courts. The Lord Chancellor will preside over an appointment ceremony at Westminster Hall on 21 March 2022.

Elizabeth founded the International Law Programme at Chatham House and is an academic expert member of Doughty Street Chambers. She was a legal adviser in the United Kingdom diplomatic service between 1974 and 2003. Between 1994 and 1997 she was the Legal Adviser to the United Kingdom mission to the United Nations in New York. She also took part in the negotiations for the establishment of the International Criminal Court.

Throughout her career, Elizabeth has worked to strengthen the role of international law in reducing global tensions, addressing cross-border challenges and promoting individual liberty, including through influential publications at the Institute such as The Chatham House Principles of International Law on the Use of Force in Self-Defence. 

Robin Niblett CMG, Director and Chief Executive of Chatham House said:

‘We are delighted by this award which recognizes Elizabeth’s outstanding contribution to the field of international law, both in government and – on a continuing basis – through the International Law Programme at Chatham House.’

How are war crimes prosecuted? Explainer Video NCapeling 26 April 2022

Explaining what war crimes are and how, in the circumstances of Ukraine, could war crimes be prosecuted.

The Geneva Conventions and Protocol 1 describe what they call ‘grave breaches’ of international humanitarian law, and both Ukraine and Russia are parties to these treaties.

Grave breaches include directly attacking civilians and launching an indiscriminate attack affecting the civilian population or civilian property.

Many states and the International Criminal Court (ICC) also have the possibility to prosecute a wider set of war crimes although, in the past, states have not prosecuted many such crimes committed outside their own territory.

Neither Russia nor Ukraine is a party to the ICC Statute, but Ukraine did declared it accepted the Court’s jurisdiction for crimes on its territory, and and investigations have now started.

But there are several problems to be overcome to achieve successful prosecutions, such as the collection and preservation of evidence, proof of the intent of the suspects in the heat of war, how to be arrest suspects, and the issue of immunity.

Cyberspace governance at the United Nations 18 January 2023 — 3:00PM TO 4:00PM Anonymous (not verified) 30 November 2022 Online

How can member states achieve lasting, adaptable, and meaningful success in cyberspace governance at the United Nations?

Now in its second iteration, the Open-ended Working Group on Information and Communications Technologies (OEWG) has been a space for United Nations member states to discuss the use, regulation and governance of cyberspace since 2019.

The progress of this forum in shaping cyberspace and its governance is evidenced by two consensus reports including a framework for responsible state behaviour in cyberspace and, more recently, plans for a Programme of Action. 
 
However, the true impact of these UN processes in limiting the threats of ICTs to international peace and security is contingent upon operationalizing the consensus at the international level and reflecting it in national policies and practices.

Pervasive challenges continue to hamper operationalization efforts, including differences in national capacities and capabilities, and divergences in national perspectives regarding the application of international law to cyberspace.

So, how can member states overcome these challenges and set this vital forum up for lasting, adaptable and meaningful success? What role does ‘multi-stakeholderism’ play in realizing responsible state behaviour in cyberspace?

With a dual focus on cyber capacity building and international law, this event considers how these two elements interact and intersect, how discussions on them could progress in the UN space and outside it and how the two contribute to a safer and more secure cyberspace for all. 
 
This event is organized jointly by the International Security and International Law Programmes at Chatham House to launch Phase 2 of the project ‘Cyberspace4All: Towards an inclusive approach to cyber governance’ which is funded by the Ministry of Foreign Affairs of the Netherlands.

Seven ways Russia’s war on Ukraine has changed the world Feature jon.wallace 17 February 2023

Chatham House experts examine the shifts in geopolitical alliances, security, energy, and supply chains and whether these changes are likely to be long-lasting.

President Vladimir Putin’s decision to launch a full-scale re-invasion of Ukraine one year ago was a global shock which ‘marked an abrupt end to 30 years of globalization and all the international co-operation that made that possible’ with serious implications for countries around the world, outlined Chatham House director Bronwen Maddox in her inaugural lecture.

Not only has the war threatened the stability of Europe but it has also impacted food and energy security globally including in the Middle East and Africa, creating shock waves in a world barely recovering from the COVID-19 pandemic.

CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

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