Current Opinion in Genetics & Development最新文献

B cells undergoing physiologically programmed or aberrant genomic alterations provide an opportune system to study the causes and consequences of genome mutagenesis. Activated B cells in germinal centers express activation-induced cytidine deaminase (AID) to accomplish physiological somatic hypermutation (SHM) of their antibody-encoding genes. In attempting to diversify their immunoglobulin (Ig) heavy- and light-chain genes, several B-cell clones successfully optimize their antigen-binding affinities. However, SHM can sometimes occur at non-Ig loci, causing genetic alternations that lay the foundation for lymphomagenesis, particularly diffuse large B-cell lymphoma. Thus, SHM acts as a double-edged sword, bestowing superb humoral immunity at the potential risk of initiating disease. We refer to off-target, non-Ig AID mutations — that are often but not always associated with disease — as aberrant SHM (aSHM). A key challenge in understanding SHM and aSHM is determining how AID targets and mutates specific DNA sequences in the Ig loci to generate antibody diversity and non-Ig genes to initiate lymphomagenesis. Herein, we discuss some current advances regarding the regulation of AID’s DNA mutagenesis activity in B cells.

Environment–epigenome interactions are emerging as contributors to disease risk and health outcomes. In fact, organisms outside of the laboratory are constantly exposed to environmental changes that can influence chromatin regulation at multiple levels, potentially impacting on genome function. In this review, we will summarize recent findings on how major external cues impact on 3D chromatin organization in different experimental systems. We will describe environment-induced 3D genome alterations ranging from chromatin accessibility to the spatial distribution of the genome and discuss their role in regulating gene expression.

During brain development, the sequence of developmental steps and the underlying transcriptional regulatory logic are largely conserved across species. However, the temporal unfolding of developmental programs varies dramatically across species and within a given species varies across brain regions and cell identities. The maturation of neurons in the human cerebral cortex is particularly slow and lasts for many years compared with only a few weeks for the corresponding mouse neurons. The mechanisms setting the ‘schedule’ of neuronal maturation remain unclear but appear to be linked to a cell-intrinsic ‘clock’. Here, we discuss recent findings that highlight a role for epigenetic factors in the timing of neuronal maturation. Manipulations of those factors in stem cell-based models can override the intrinsic pace of neuronal maturation, including its protracted nature in human cortical neurons. We then contextualize the epigenetic regulation of maturation programs with findings from other model systems and propose potential interactions between epigenetic pathways and other drivers of developmental rates.

Long noncoding RNAs (lncRNAs) are a class of RNA molecules exceeding 200 nucleotides in length that lack long open-reading frames. Transcribed predominantly by RNA polymerase II (>500nt), lncRNAs can undergo splicing and are produced from various regions of the genome, including intergenic regions, introns, and in antisense orientation to protein-coding genes. Aberrations in lncRNA expression or function have been associated with a wide variety of diseases, including cancer, cardiovascular diseases, diabetes, and neurodegeneration. Despite the growing recognition of select lncRNAs as key players in cellular processes and diseases, several challenges obscure a comprehensive understanding of their functional landscape. Recent technological innovations, such as in sequencing, affinity-based techniques, imaging, and RNA perturbation, have advanced functional characterization and mechanistic understanding of disease-associated lncRNAs.

It is long known that an RNA polymerase transcribing through a nucleosome can generate subnucleosomal particles called hexasomes. These particles lack an H2A–H2B dimer, breaking the symmetry of a nucleosome and revealing new interfaces. Whether hexasomes are simply a consequence of RNA polymerase action or they also have a regulatory impact remains an open question. Recent biochemical and structural studies of RNA polymerases and chromatin remodelers with hexasomes motivated us to revisit this question. Here, we build on previous models to discuss how formation of hexasomes can allow sophisticated regulation of transcription and also significantly impact chromatin folding. We anticipate that further cellular and biochemical analysis of these subnucleosomal particles will uncover additional regulatory roles.

Aberrant chromatin regulation can promote the initiation and progression of human cancer. An improved understanding of such mechanisms has resulted in the identification of cancers with an enhanced dependency on specific chromatin regulatory proteins relative to nonmalignant cell types. Hence, targeting of such complexes with small molecules has significant therapeutic potential in oncology. In recent years, several drugs have been developed and evaluated in human cancer patients, which can influence tumor biology by reprogramming of chromatin structure. In this review, we summarize several of the known mechanisms that endow cancer cells with a powerful dependency on chromatin regulation that exceeds the requirements for normal tissue homeostasis. We also summarize the remarkable small-molecule inhibitors that exploit chromatin regulator dependencies with a clear therapeutic benefit in human cancer patients.

Chromosome structure regulates DNA-templated processes such as transcription of genes. Dynamic changes to chromosome structure occur during development and in disease contexts. The cohesin complex is a molecular motor that regulates chromosome structure by generating DNA loops that bring two distal genomic sites into close spatial proximity. There are many open questions regarding the formation and dissolution of DNA loops, as well as the role(s) of DNA loops in regulating transcription of the interphase genome. This review focuses on recent discoveries that provide molecular insights into the role of cohesin and chromosome structure in gene transcription during development and disease.

During gastrulation, Hox genes are activated in a time-sequence that follows the order of the genes along their clusters. This property, which is observed in all animals that develop following a progressive rostral-to-caudal morphogenesis, is associated with changes in the chromatin structure and epigenetic profiles of Hox clusters, suggesting a process at least partly based on sequential gene accessibility. Here, we discuss recent work on this issue, as well as a possible mechanism based on the surprising conservation in both the distribution and orientation of CTCF sites inside vertebrate Hox clusters.