Illuminating the genome

Abstract

It was long assumed that our linear DNA sequence encodes all the information required to influence the development of multicellular organisms and their progeny. This notion is not surprising given the dramatic changes that occur in organisms when minor changes are made in the genetic code. However, the past few decades have challenged this simple concept, igniting a renaissance in nuclear cell biology.Within the nucleus, the genome is not laid flat but is tightly packaged into dynamic chromatin. Changes in chromatin structure and organization add a layer of complexity to gene regulation beyond DNA. Epigenetic regulation involving modifications of histones and DNA, as well as nucleosome remodeling, and noncoding RNA (ncRNA) can all contribute to changes in the spatial and structural organization of chromatin within the nucleus. Indeed, these changes can determine how tightly wound the DNA is around histone proteins, which can in turn switch on or off gene programs. While the parts involved in regulating the dynamic states of chromatin structure are well known, recent breakthroughs in genomic technologies have led to an unprecedented growth in our understanding of their biological functions and molecular mechanisms. In appreciation of this rapid development, this special issue of Trends in Cell Biology focuses on recent breakthroughs in our understanding of how the dynamic processes of epigenetic and chromatin components integrate to regulate critical cellular processes.The regulation of cell fate is likely one of the most important factors impacting the development of multicellular organisms. Cell type-specific gene expression patterns that are regulated during differentiation and morphogenesis are fundamental for maintaining cell identity. Key to this process is the binding of transcription factors to enhancer elements or to recently identified, large enhancer regions dubbed ‘super-enhancers.’ Yali Xu and Christopher Vakoc discuss a recent study suggesting that the activation of NF-kB directs the organization of super-enhancers, thereby providing a rationale for why these genes converge to control inflammation in specific cell types. With the growing list of enhancers involved in regulating specific gene expression patterns, it has become crucial to understand the mechanisms involved. While once considered to only activate its nearest promoter, enhancers can also impact promoter activity in three-dimensional space. Bas van Steensel and colleagues provide an introduction for how enhancers choose their target promoter. Going a step further, Elena Gómez-Díaz and Victor Corces examine how nuclear architectural proteins contribute to the three-dimensional organization of chromatin to bring together regulatory elements and their targets to influence cell fate. The field has also begun to appreciate the role of long noncoding RNAs (lncRNAs) in shaping chromatin architecture and mediating gene expression. Mitchell Guttman and colleagues suggest a provocative model in which lncRNAs act as organization centers to control gene expression.Along with transcription, epigenetic modifications that influence chromatin structure can also affect genome stability. Roger Greenberg and colleagues discuss recent progress in defining the mechanisms by which chromatin structure can regulate DNA repair pathway choice. Christian Gerhold and Susan Gasser review the structures and nucleosome-binding modes of the INO80 family of nucleosome remodelers as a rationale for their diverse activities in such processes as gene regulation and DNA repair. Furthermore, Paul Talbert and Steven Henikoff propose roles for histone variants in and beyond their role in repair, citing examples by which histone variants mediate environmental perturbations such as temperature, DNA damage, and host defense.The impact of epigenetics does not necessarily end once a cell divides. The idea that epigenetic marks can be transmitted from one generation to the next remains controversial. However, studies of germline reprogramming are shedding light on the mechanisms by which epigenetic information survives through development and across generations. Danny Reinberg and colleagues take us on a journey of epigenetic inheritance, exploring ways histone marks are inherited through the paternal lineage.The reviews discussed above clearly demonstrate the positive impact that chromatin dynamics has on a cell, but not all changes are beneficial. It is well accepted that changes in the length of telomeres, specialized chromatin structures, play an essential role in chromosome protection and in tumorigenesis. Shortened telomeres are linked to senescence while extension and maintenance of telomere length are associated with cancer cell proliferation. One mechanism to maintain telomere length is through the exchange of telomeric DNA between chromosomes in a pathway termed alternative lengthening of telomeres (ALT). Roderick O'Sullivan and Genevieve Almouzni examine recently identified mutations in chromatin and epigenetic modifications that are associated with ALT and propose that telomere length may be epigenetically regulated. Beyond telomeres, aberrations in other epigenetic modifications have also been associated with aging and cancer. Jose Gil and Ana O’Loghlen highlight the diverse actions of Polycomb group proteins in cell fate, with a focus on PRC1 diversity. By interfering with chromatin structure, PRC1 may contribute to the bypass of senescence and onset of tumor progression. Tom Misteli and colleagues further underscore how these epigenetic changes impact chromatin, suggesting that the chromatin states observed in aging may contribute to tumorigenesis.The reviews discussed above emphasize how chromatin dynamics impact diverse cellular processes, with much of the data supporting these findings being derived from populations of cells. However, single cells within these populations may express variable levels of epigenetic processes that could ultimately impact how we understand the heritability of phenotypic traits to progeny. Poonam Bheda and Robert Schneider explore how single cell analysis approaches can clarify the degree of epigenetic inheritance by tracing changes at specific loci in dividing cells and their stability through multiple generations.Thanks in part to the explosion of new techniques to investigate chromatin states, the field of nuclear cell biology has seen a revitalization that will likely continue for many years. I hope that these reviews provide inspiration for moving the field forward. I would like to thank all the authors and reviewers for their contributions to this special issue and hope you enjoy reading it. I welcome your comments and ideas; you can always contact us with your feedback or questions at [email protected] or @TrendsCellBio. It was long assumed that our linear DNA sequence encodes all the information required to influence the development of multicellular organisms and their progeny. This notion is not surprising given the dramatic changes that occur in organisms when minor changes are made in the genetic code. However, the past few decades have challenged this simple concept, igniting a renaissance in nuclear cell biology. Within the nucleus, the genome is not laid flat but is tightly packaged into dynamic chromatin. Changes in chromatin structure and organization add a layer of complexity to gene regulation beyond DNA. Epigenetic regulation involving modifications of histones and DNA, as well as nucleosome remodeling, and noncoding RNA (ncRNA) can all contribute to changes in the spatial and structural organization of chromatin within the nucleus. Indeed, these changes can determine how tightly wound the DNA is around histone proteins, which can in turn switch on or off gene programs. While the parts involved in regulating the dynamic states of chromatin structure are well known, recent breakthroughs in genomic technologies have led to an unprecedented growth in our understanding of their biological functions and molecular mechanisms. In appreciation of this rapid development, this special issue of Trends in Cell Biology focuses on recent breakthroughs in our understanding of how the dynamic processes of epigenetic and chromatin components integrate to regulate critical cellular processes. The regulation of cell fate is likely one of the most important factors impacting the development of multicellular organisms. Cell type-specific gene expression patterns that are regulated during differentiation and morphogenesis are fundamental for maintaining cell identity. Key to this process is the binding of transcription factors to enhancer elements or to recently identified, large enhancer regions dubbed ‘super-enhancers.’ Yali Xu and Christopher Vakoc discuss a recent study suggesting that the activation of NF-kB directs the organization of super-enhancers, thereby providing a rationale for why these genes converge to control inflammation in specific cell types. With the growing list of enhancers involved in regulating specific gene expression patterns, it has become crucial to understand the mechanisms involved. While once considered to only activate its nearest promoter, enhancers can also impact promoter activity in three-dimensional space. Bas van Steensel and colleagues provide an introduction for how enhancers choose their target promoter. Going a step further, Elena Gómez-Díaz and Victor Corces examine how nuclear architectural proteins contribute to the three-dimensional organization of chromatin to bring together regulatory elements and their targets to influence cell fate. The field has also begun to appreciate the role of long noncoding RNAs (lncRNAs) in shaping chromatin architecture and mediating gene expression. Mitchell Guttman and colleagues suggest a provocative model in which lncRNAs act as organization centers to control gene expression. Along with transcription, epigenetic modifications that influence chromatin structure can also affect genome stability. Roger Greenberg and colleagues discuss recent progress in defining the mechanisms by which chromatin structure can regulate DNA repair pathway choice. Christian Gerhold and Susan Gasser review the structures and nucleosome-binding modes of the INO80 family of nucleosome remodelers as a rationale for their diverse activities in such processes as gene regulation and DNA repair. Furthermore, Paul Talbert and Steven Henikoff propose roles for histone variants in and beyond their role in repair, citing examples by which histone variants mediate environmental perturbations such as temperature, DNA damage, and host defense. The impact of epigenetics does not necessarily end once a cell divides. The idea that epigenetic marks can be transmitted from one generation to the next remains controversial. However, studies of germline reprogramming are shedding light on the mechanisms by which epigenetic information survives through development and across generations. Danny Reinberg and colleagues take us on a journey of epigenetic inheritance, exploring ways histone marks are inherited through the paternal lineage. The reviews discussed above clearly demonstrate the positive impact that chromatin dynamics has on a cell, but not all changes are beneficial. It is well accepted that changes in the length of telomeres, specialized chromatin structures, play an essential role in chromosome protection and in tumorigenesis. Shortened telomeres are linked to senescence while extension and maintenance of telomere length are associated with cancer cell proliferation. One mechanism to maintain telomere length is through the exchange of telomeric DNA between chromosomes in a pathway termed alternative lengthening of telomeres (ALT). Roderick O'Sullivan and Genevieve Almouzni examine recently identified mutations in chromatin and epigenetic modifications that are associated with ALT and propose that telomere length may be epigenetically regulated. Beyond telomeres, aberrations in other epigenetic modifications have also been associated with aging and cancer. Jose Gil and Ana O’Loghlen highlight the diverse actions of Polycomb group proteins in cell fate, with a focus on PRC1 diversity. By interfering with chromatin structure, PRC1 may contribute to the bypass of senescence and onset of tumor progression. Tom Misteli and colleagues further underscore how these epigenetic changes impact chromatin, suggesting that the chromatin states observed in aging may contribute to tumorigenesis. The reviews discussed above emphasize how chromatin dynamics impact diverse cellular processes, with much of the data supporting these findings being derived from populations of cells. However, single cells within these populations may express variable levels of epigenetic processes that could ultimately impact how we understand the heritability of phenotypic traits to progeny. Poonam Bheda and Robert Schneider explore how single cell analysis approaches can clarify the degree of epigenetic inheritance by tracing changes at specific loci in dividing cells and their stability through multiple generations. Thanks in part to the explosion of new techniques to investigate chromatin states, the field of nuclear cell biology has seen a revitalization that will likely continue for many years. I hope that these reviews provide inspiration for moving the field forward. I would like to thank all the authors and reviewers for their contributions to this special issue and hope you enjoy reading it. I welcome your comments and ideas; you can always contact us with your feedback or questions at [email protected] or @TrendsCellBio.