Review
Abstract
As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain–containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases. They additionally include the H3K4/9-preferential demethylase LSD1 and the H3K4-, H3K27-, and H3K36-preferential KDM5, KDM6, and KDM2 demethylase subfamilies, respectively. This Review discusses the results of recent clinical and preclinical studies relevant to all of these existing and potential therapies. It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant “histone code” metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.
Authors
Sarah Gold, Ali Shilatifard
Abstract
Substance use disorders (SUDs) are highly prevalent and associated with excess morbidity, mortality, and economic costs. Thus, there is considerable interest in the early identification of individuals who may be more susceptible to developing SUDs and in improving personalized treatment decisions for those who have SUDs. SUDs are known to be influenced by both genetic and environmental factors. Polygenic scores (PGSs) provide a single measure of genetic liability that could be used as a biomarker in predicting disease development, progression, and treatment response. Although PGSs are rapidly being integrated into clinical practice, there is little information to guide clinicians in their responsible use and interpretation. In this Review, we discuss the potential benefits and pitfalls of the use of PGSs in the clinical care of SUDs, highlighting current research. We also provide suggestions for important considerations prior to implementing the clinical use of PGSs and recommend future directions for research.
Authors
Rachel L. Kember, Christal N. Davis, Kyra L. Feuer, Henry R. Kranzler
Abstract
Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.
Authors
Bernard Le Foll, Victor M. Tang, Sergio Rueda, Leanne V. Trick, Isabelle Boileau
Abstract
Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction–associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.
Authors
Eric O. Johnson, Heidi S. Fisher, Kyle A. Sullivan, Olivia Corradin, Sandra Sanchez-Roige, Nathan C. Gaddis, Yasmine N. Sami, Alice Townsend, Erica Teixeira Prates, Mirko Pavicic, Peter Kruse, Elissa J. Chesler, Abraham A. Palmer, Vanessa Troiani, Jason A. Bubier, Daniel A. Jacobson, Brion S. Maher
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.
Authors
Ohad Oren, Aeron M. Small, Peter Libby
Abstract
Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.
Authors
Koichi Takahashi, Daisuke Nakada, Margaret Goodell
Abstract
Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.
Authors
William G. Dunn, Matthew A. McLoughlin, George S. Vassiliou
Abstract
Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.
Authors
DeLisa Fairweather, Danielle J. Beetler, Elizabeth J. McCabe, Scott M. Lieberman
Abstract
Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.
Authors
Erin Mihealsick, Anna Word, Eileen P. Scully
Abstract
Depression and multiple musculoskeletal disorders are overrepresented in women compared with men. Given that depression is a modifiable risk factor and improvement of depressive symptoms increases positive outcomes following orthopedic intervention, efforts to improve clinical recognition of depressive symptoms and increased action toward ameliorating depressive symptoms among orthopedic patients are positioned to reduce complications and positively affect patient-reported outcomes. Although psychosocial factors play a role in the manifestation and remittance of depression, it is also well appreciated that primary biochemical changes are capable of causing and perpetuating depression. Unique insight for novel treatments of depression may be facilitated by query of the bidirectional relationship between musculoskeletal health and depression. This Review aims to synthesize the diverse literature on sex, depression, and orthopedics and emphasize the potential for common underlying biological substrates. Given the overrepresentation of depression and musculoskeletal disorders among women, increased emphasis on the biological drivers of the co-occurrence of these disorders is positioned to improve women’s health.
Authors
Mackenzie Newman, Henry J. Donahue, Gretchen N. Neigh
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