Jennifer L. Macdonald
May 1, 2005; 46:1061-1067
Methods

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

DL Brasaemle
Nov 1, 1997; 38:2249-2263
Articles

K Schoonjans
May 1, 1996; 37:907-925
Reviews

IJ Goldberg
Apr 1, 1996; 37:693-707
Reviews

JP Segrest
Feb 1, 1992; 33:141-166
Reviews

Saverio Cinti
Nov 1, 2005; 46:2347-2355
Research Articles

JE Hixson
Mar 1, 1990; 31:545-548
Articles

Announcing Design Resonance in an Age of Crisis News Release sysadmin 1 June 2020

London Design Biennale and Chatham House announce Design Resonance in an Age of Crisis, which calls for action by designers around the world to create radical design solutions to critical problems across four key areas: Health, Environment, Society and Work.

Design In An Age of Crisis - Open Call News Release sysadmin 21 July 2020

Chatham House and London Design Biennale announce full details of 'Design In An Age of Crisis,' a global Open Call for radical design thinking.

Chatham House Prize: Malawi Judges Win for Election Work News Release NCapeling 23 October 2020

Malawi’s constitutional court judges have won the 2020 Chatham House Prize in recognition of their 'courage and independence in the defence of democracy'.

Strengthening Our Commitment to the Next Generation News Release NCapeling 9 November 2020

Panel of Young Advisers and Queen Elizabeth II Academy Ambassadors underscore our drive to reach, engage and inspire young people to change their world.

Design in an Age of Crisis Launches News Release jon.wallace 13 January 2021

Design open call receives 500 submissions from over 50 countries across six continents.

Supporting Next Generation of Leaders in Sustainability News Release NCapeling 28 January 2021

A new programme offering paid internships for young people who are passionate about social, economic, and environmental sustainability has been launched.

Geopolitical shifts and evolving social challenges – what role for human rights? 29 June 2021 — 3:00PM TO 4:30PM Anonymous (not verified) 10 June 2021 Online

Speakers reflect on some of the key themes that will influence the future of human rights.

Please click on the below link to confirm your participation and receive your individual joining details from Zoom for this event. You will receive a confirmation email from Zoom, which contains the option to add the event to your calendar if you so wish.

Shifts in geopolitical power and the rise of authoritarianism are disrupting the dynamics for making progress on human rights globally.

At the same time, the relevance of the global human rights framework is being called into question by some of our most acute social challenges – rapidly evolving technology, deepening inequality and the climate crisis.

Chatham House’s Human Rights Pathways project is exploring how alliances, strategies and institutions are adapting, and will need to evolve, to strengthen human rights protection in this increasingly contested and complex global environment.

At this panel event speakers reflect on some of the key themes that will influence the future of human rights, including the long-term impacts of the pandemic, the place of human rights diplomacy in the new geopolitics, the relevance of human rights to social movements, and the potential of human rights law to galvanise efforts on urgent challenges such as the climate crisis.

Why the next generation is key to protecting human rights Expert comment LToremark 23 June 2021

Strengthening youth participation in public affairs is essential to building inclusive and democratic societies that respect human rights.

Young people have always been drivers of social and economic reform, and today’s global youth population is more numerous and interconnected than ever before. While they have been at the forefront of civic rights movements in recent years, young people are largely excluded from discussions around human rights norms and how to monitor their protection and defence.

Young people are consistently underrepresented in intergovernmental mechanisms and national dialogues, which not only squanders their potential to contribute to effective solutions but also risks disengagement and disillusionment with multilateralism more broadly, at a time when many are already warning of the fraying of the international liberal order. Although there are actors and initiatives working to lift barriers to youth participation in governance – such as the UN Secretary-General’s Envoy on Youth, Jayathma Wickramanayake, or the UN 2016 Not Too Young To Run campaign – these efforts tend to fall short in effecting real change and rarely translate into institutionalized procedures.

While ‘the youth’ is a heterogenous group, comprising different ages, ethnicities, national identities and interests, their participation in realizing human rights is essential to addressing the current challenges and possibilities of human rights for future generations. This will help foster more effective solutions to rights-related challenges, re-build trust in the international human rights framework among younger demographics and broaden and deepen commitments to human rights across generations.

Human rights policies and the online environment

Young people tend to be more technologically literate than their predecessors and also represent the majority of internet users and social media consumers in many countries. They can therefore play a key role in innovating and imagining rights-based solutions to emerging problems for the human rights framework, such as illegitimate collection of data by governments and companies, microtargeting by online platforms, and the sharing of harmful content online. In many cases, international human rights practices have failed to keep pace with these changes and the challenges they bring.

Younger demographics may also approach these novel human rights issues from different starting points. For example, a UK study found that 30 per cent of 18-24 year-olds were ‘unconcerned’ about data privacy compared with only 12 per cent of those aged 55-64, and it has been shown that younger people tend to be more discerning of fake news compared to older generations. There may be a need for human rights institutions and practitioners to acknowledge and bridge these gaps in perspective and understanding to ensure long-term support for proposed solutions.

International cooperation for human rights protection

It has been suggested that young people have reaped the benefits of previous human rights-based policy reforms and have a strong sense of what rights they are entitled to and why these need to be protected through an international framework. Young people are also generally more supportive of multilateralism compared to their older counterparts, as demonstrated by a 2020 survey by Pew Research Center on global attitudes, which showed that 72 per cent of respondents aged 18-29 stated they have a favourable view of the UN, compared with 58 per cent of respondents aged 50 and older.

At a recent Chatham House workshop, young participants from countries as diverse as Lebanon, Kenya and the United States expressed concern that growing hostility towards globalization threatens to undo progress in human rights standards and multilateralism more broadly, progress that they have seen and benefitted from. The rise of nationalist and populist parties has also seen countries shift their attention inwards, as evidenced by former president Trump’s decision to withdraw the US from the Paris Agreement on climate change, and threats by Brazil’s president, Jair Bolsonaro, to follow suit.

Engaging more actively with younger individuals on global human rights reform will help ensure the long-term relevance of multilateral cooperation as well as domestic buy-in of human rights commitments.

Awareness of the interconnectivity of global problems

Young people’s proficiency on online platforms has enabled greater coordination and knowledge sharing without geographical constraints, allowing young activists – like Greta Thunberg – to inspire global movements and foster online discussions about intersectional solutions to modern-day challenges.

This intersectional and transnational lens will be a vital component of building solutions to politically or historically complex issues and can be leveraged to foster better understanding of competing human rights claims relating to issues such as land re-distribution in South Africa or limitations on freedom of movement during the COVID-19 pandemic. These democratic forums and platforms will ultimately help build a global community committed to and engaged with human rights.

Capturing the next generation’s potential

With these concerns and areas of potential in mind, how can human rights institutions and mechanisms create more meaningful avenues for youth input? 

Recent Chatham House research has suggested that multilateral institutions’ efforts to engage youth has often taken the form of ‘superficial listening’, for example inviting a high-profile youth actor to a one-off event or appointing youth delegates who are not able to participate in formal discussions or mainstream governance forums. While encouraging youth participation in meetings focused on human rights can lead to positive change, tokenism can discourage future engagement and dilute the effectiveness of the forums in question.

Capitalizing on the potential of the next generation can be achieved through integrating youth councils and advisers into national and international human rights policy processes, as well as human rights institutions. A few replicable models are already operational, such as the Y7 and the Y20 delegations – the official youth engagement groups for the G7 and G20 – that advance evidence-based proposals to world leaders ahead of the G7 and G20 summits.

At the domestic level, grassroots youth-led movements can help bridge the gap between local constituencies and international policymakers, with youth activists on the ground helping to implement human rights standards and fighting against the spread of misinformation. Strong local networks and civic spaces are essential for pushing back against human rights abuses, and youth activists should be mobilized to connect the efforts of domestic and international bodies to the real issues on the ground; for example, canvassing grassroots youth networks on domestic and traditional customs before implementing development agendas around women’s rights.

As well as providing insertion points for youth policy actors, human rights institutions must communicate their goals more effectively to younger generations and promote intergenerational and inclusive dialogue, for example by holding virtual consultations that  give access to individuals from different backgrounds. Similarly, they should ask young people about their priorities for human rights reform using regular and accessible surveys or by sharing information on online platforms regularly used by this demographic. This will ensure lasting buy-in from the next generation, essential for the relevance and sustainability of the human rights framework in the years to come.

This piece draws upon insights gathered at a workshop hosted by Chatham House in March 2021, which brought together the Institute’s networks of next generation groups including representatives of the QEII Academy Ambassadors, the Panel of Young Advisers, and the Common Futures Conversations community, as well as young members from the South African Institute of International Affairs.

Challenges of AI Explainer jon.wallace 22 March 2022

What are the practical, legal and ethical implications of artificial intelligence (AI) and how can regulation help meet these challenges?

This article explains the challenges associated with the funding, development, supply and regulation of artificial intelligence (AI). It deals with narrow AI, that is systems and applications that are task-specific.

The article is not concerned with the concept of artificial general intelligence, or AGI, that is an AI which could meet and exceed the full capabilities of the human mind in the future.

Definition of AI

There is no universally accepted definition of AI, but in the UK’s Industrial Strategy White Paper, AI is defined as ‘technologies with the ability to perform tasks that would otherwise require human intelligence’. 

AI makes decisions using algorithms that either follow rules or, in the case of machine learning, review large quantities of data to identify and follow patterns. Because machine learning consists of multiple layers, and machines develop their own learning and patterns, it is opaque compared to traditional rule-following computing.

Today AI applications are common in many economic activities including online shopping and advertising, web search, digital personal assistants, language translation, smart homes and infrastructure, health, transport and manufacturing. 

Risks and benefits of AI

AI has the potential to bring huge advantages, for example in medical science, education, food and aid distribution, more efficient public transport and in tackling climate change. 

Used well, it could help humanity meet the UN’s 2030 Sustainable Development Goals and make many processes swifter, fairer and more efficient. It is a technology which is likely to be as transformative to human history as was the Industrial Revolution.

However, there are serious ethical, safety and societal risks associated with the rapid growth of AI technologies. 

Will AI be a tool that makes rich people richer? Will it exaggerate bias and discrimination? Will AI decision-making create a less compassionate society? Should there be limits to what decisions an AI system can take autonomously, from overtaking a car on the motorway to firing a weapon?

And if AI goes wrong – for example if a self-driving car has an accident – who should be liable? 

To ensure AI is used safely and fairly, up-to-date and rigorous regulation is needed. 

Regulation of AI

AI creates serious regulatory challenges due to the way it is funded, researched and developed.  

The private sector drives progress in AI, and governments mostly rely on big tech companies to build their AI software, furnish their AI talent, and achieve AI breakthroughs. In many respects this is a reflection of the world we live in, as big tech firms have the resources and expertise required.

However, without government oversight the future application of AI’s extraordinary potential will be effectively outsourced to commercial interests. That outcome provides little incentive to use AI to address the world’s greatest challenges, from poverty and hunger to climate change.

Government policy on AI

Currently governments are playing catch-up as AI applications are developed and rolled out. Despite the transnational nature of this technology, there is no unified policy approach to AI regulation, or to the use of data. 

It is vital that governments provide ‘guardrails’ for private sector development through effective regulation. But this is not yet in place, either in the US (where the largest amount of development is taking place) or in most other parts of the world. This regulation ‘vacuum’ has significant ethical and safety implications for AI. 

Some governments fear that imposing stringent regulations will discourage investment and innovation in their countries and lose them a competitive advantage. This attitude risks a ‘race to the bottom’, where countries compete to minimize regulation in order to lure big tech investment. 

The EU and UK governments are beginning to discuss regulation but plans are still at an early stage. Probably the most promising approach to government policy on AI is the EU’s proposed risk-based approach. It would ban the most problematic uses of AI, such as AI that distorts human behaviour or manipulates citizens through subliminal techniques. 

And it would require risk management and human oversight of AI that poses high risk to safety or human rights, such as AI used in critical infrastructure, credit checks, recruitment, criminal justice, and asylum applications.

Meanwhile, the UK is keen to see the establishment of an AI assurance industry that would provide kitemarks (or the equivalent) for AI that meets safety and ethical standards.

Despite these policy developments, there remain fundamental questions about how to categorize and apply risk assessments, what an AI rights-based approach could look like, and the lack of inclusivity and diversity in AI.

AI ethical issues

AI has serious ethical implications. Because AI develops its own learning, those implications may not be evident until it is deployed. The story of AI is littered with ethical failings: with privacy breaches, with bias, and with AI decision-making that could not be challenged.

It’s therefore important to identify and mitigate ethical risks while AI is being designed and developed, and on an ongoing basis once it is in use. 

But many AI designers work in a competitive, profit-driven context where speed and efficiency are prized and delay (of the kind implied by regulation and ethical review) is viewed as costly and therefore undesirable. 

Designers may also not have the training, tools or capacity to identify and mitigate ethical issues. The majority are from an engineering or computing background, and do not reflect the diversity in society.

Shareholders and senior management will also naturally be hostile to criticism which could affect profits.

Once an AI application has been designed, it is often sold to companies to fulfil a task (for example, sifting employment applicants) without the buyer being able to understand how it works or what risks may come with it.

Ethical frameworks for AI

Some international bodies have made efforts to create an ethical framework for AI development, including UNESCO’s Recommendation on the Ethics of Artificial Intelligence, and the IEEE’s Global Initiative on Ethics of Autonomous and Intelligent Systems. And some companies have developed their own ethical initiatives.

But each of these proposals naturally overlaps, is slightly different and is voluntary. They set out principles for creating ethical AI, but provide no accountability in the event that an AI goes wrong.

Ethical roles in the AI industry are a potentially important new profession, but the field is underfunded and under resourced. There is widespread agreement that ethics is important, but a lack of consensus on how it should be enforced.

Government use of AI

It’s equally important that the way governments use AI is understood, consensual and ethical, complying with human rights obligations. Opaque practices by governments may feed the perception of AI as a tool of oppression. 

China has some of the clearest regulation of AI private industry in the world, but the way the government has deployed AI tools in the surveillance of its citizens has serious civil liberties implications.

China’s exports of AI to other countries are increasing the prevalence of government surveillance internationally.

Privacy and AI

Probably the greatest challenge facing the AI industry is the need to reconcile AI’s need for large amounts of structured or standardized data with the human right to privacy. 

AI’s ‘hunger’ for large data sets is in direct tension with current privacy legislation and culture. Current law, in the UK and Europe limits both the potential for sharing data sets and the scope of automated decision-making. These restrictions are limiting the capacity of AI. 

During the COVID-19 pandemic, there were concerns that it would not be possible to use AI to determine priority allocation of vaccines. (These concerns were allayed on the basis that GPs provided oversight on the decision-making process.)

More broadly, some AI designers said they were unable to contribute to the COVID-19 response due to regulations that barred them from accessing large health data sets. It is at least feasible that such data could have allowed AI to offer more informed decisions about the use of control measures like lockdowns and the most effective global distribution of vaccines.

Better data access and sharing are compatible with privacy, but require changes to our regulation. The EU and UK are considering what adjustments to their data protection laws are needed to facilitate AI while protecting privacy.

Geopolitical corporate responsibility can drive change Expert comment NCapeling 26 July 2022

Russia’s long invasion of Ukraine is testing the commitment of business, but this could see the emergence of a new pillar of support for the rules-based international order.

The massive exit of more than 1,000 international companies from Russia has surpassed – by a factor of nearly ten in merely four months – the number which pulled out of apartheid-led South Africa over an entire decade.

These company exits extend beyond those industries targeted for sanctions – oil and gas, banks and financial services, aerospace, and certain technology sectors – to include hundreds in consumer products ranging from Levi’s and H&M clothing to Coca-Cola and McDonalds. Many of these companies may wish to return to a post-conflict – or post-Putin – Russia, while a few have already sold their Russian operations, as McDonald’s has to an existing Siberian licensee.

Both reputational and operational factors are driving the huge exodus: reputational as companies have chosen to disassociate themselves from Putin’s regime; operational as transportation routes and supply chains have been interrupted.

Few of these companies have made explicit the principles at stake, while many still face ‘tricky legal, operational and ethical considerations’ and some have kept operations in place. But the collective impact of the exit in response to Russia’s affront to international law has sent shockwaves around the world.

Current issues and future implications

Minds now turn to whether this exodus sets a blueprint for the future, and how companies having to make complex and sensitive risk assessments and global business planning decisions can address both current issues as well as similar future challenges.

The new Declaration from the Business for Ukraine Coalition – an international civil society initiative of organizations and individuals – encourages companies to reinforce ‘responsible exit’ from Russia ‘in response to its unprovoked, full-scale war on Ukraine’.

The declaration’s objective is to ‘block access to the economic and financial resources enabling Russian aggression’ and it urgently calls on companies that have terminated or suspended their business operations and relationships to ‘stand by those commitments until the territorial sovereignty of Ukraine within internationally recognized borders is restored.’

It also states companies yet to terminate or suspend operations in Russia should do so unless they can demonstrate through due diligence that their provision of ‘essential’ services or products – such as medicines – meet critical humanitarian needs.

The 2022 Edelman Trust Barometer Special Report: The Geopolitical Business suggests Ukraine represents an inflection point posing ‘a new test’ for business. According to an online survey of 14,000 respondents in 14 countries, including employees, NGOs, and other stakeholders, there is a ‘rising call’ for business to be more engaged in geopolitics, with CEOs ‘expected to shape policy’ on societal and geopolitical issues.

Such expectations have been intensifying with the impetus of the combined stakeholder capitalism and corporate purpose agenda, even as a political backlash in the US against the environmental, social, and governance (ESG) movement linking institutional investors and multinational corporations gains momentum.

The emergence of corporate activism is a further development – partly driven by employees and accelerated during the pandemic – on issues of economic inequality, racial injustice, and gender equality, as well as the climate crisis.

When considering what broader purpose should drive this corporate geopolitical engagement, the Business for Ukraine Declaration offers an answer, calling Russia’s aggression ‘an attack on the rules-based international order which must be protected to ‘safeguard the international community and the global economy.’

This points to broader interests and values at stake in the Russian war on Ukraine because supporting the rules-based international order can become the basis of a new geopolitical corporate responsibility. Business, especially multinational corporations and institutional investors, fundamentally depend on and have enormously benefitted from this order.

Economic development needs a stable rules-based international order

Trade and investment, entrepreneurship, and innovation – the sinews of economic development – depend on predictable, rational behaviour by states at home and abroad. Individual companies and entire industries share a stake in upholding this order at a time when its stability and even legitimacy is undergoing a severe challenge.

The rules-based international order has evolved since the adoption of the UN Charter in 1945, the Universal Declaration of Human Rights in 1948, and the establishment of the standards, norms and institutions that reflect and reinforce these lodestars. It defines the international community, the rule of law, accountable governance, civic freedoms, and human rights within nations. It also supports national self-determination, sovereignty, and the disavowal of the use of force to alter borders among nations, and it provides accountability for genocide, crimes against humanity, and war crimes.

Business has a fundamental stake in the international order as the framework for stability, prosperity, open societies, and markets.

A new geopolitical corporate responsibility does not need to become a doctrine but can instead be an agenda to support the international rules-based order under stress. Such an agenda may help multinationals deal with expectations they already face, such as:

Avoiding situations where they cause, contribute, or are directly linked to human rights abuses. This objective is enshrined in the UN Guiding Principles on Business and Human Rights and companies can be further informed by the new UN Guide to Heightened Human Rights Due Diligence for Business in Conflict-Affected Contexts.

Committing to the ‘shared space’ of the rule of law, accountable governance, civic freedoms, and human rights. These are both the enablers of civil society and the underpinning of sustainable and profitable business and investment environments. The Chatham House synthesis paper The role of the private sector in protecting civic space sets forth the rationale for companies to defend these vital elements.

Supporting peace, justice, and strong institutions both within nations and across the international community as set forth by UN Sustainable Development Goal 16. The SDG 16 Business Framework: Inspiring Transformational Governance shows how companies, as well as national governments and international institutions, can contribute to these building blocks of stability and prosperity.

Demonstrating corporate responsibility at the national and geopolitical levels to enhance equity, transparency, and accountability. Multinationals are already challenged to accept minimum corporate taxation within and across jurisdictions, curb excessive executive compensation, endorse mandatory disclosure of environmental and human rights due diligence, and strengthen corporate governance of ESG risks and responsibilities, including with respect to human rights.

Diminishing inequality by tackling poverty and ensuring sustainability by arresting the climate crisis. Alongside governments and international institutions, the business community already faces increasing pressure to improve its efforts in these areas.

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.

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.

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.

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

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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