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The alternative use of transcription start sites (TSSs) regulates the production of distinct mRNA isoforms, which have crucial roles in both physiological and pathological contexts. Recent technological advances have provided deeper insights into the role of TSSs in the regulation of co-transcriptional and post-transcriptional RNA processing. We discuss the impact and possible mechanisms of the crosstalk between transcription and co-transcriptional RNA processing, especially 3′-end site selection. Alternative transcription start site usage (ATSS) is a widespread regulatory strategy that enables genes to choose between multiple genomic loci for initiating transcription. This mechanism is tightly controlled during development and is often altered in disease states. In this review, we examine the growing evidence highlighting a role for transcription start sites (TSSs) in the regulation of mRNA isoform selection during and after transcription. We discuss how the choice of transcription initiation sites influences RNA processing and the importance of this crosstalk for cell identity and organism function. We also speculate on possible mechanisms underlying the integration of transcriptional and post-transcriptional processes. Alternative transcription start site usage (ATSS) is a widespread regulatory strategy that enables genes to choose between multiple genomic loci for initiating transcription. This mechanism is tightly controlled during development and is often altered in disease states. In this review, we examine the growing evidence highlighting a role for transcription start sites (TSSs) in the regulation of mRNA isoform selection during and after transcription. We discuss how the choice of transcription initiation sites influences RNA processing and the importance of this crosstalk for cell identity and organism function. We alsospeculate on possible mechanisms underlying the integration of transcriptional and post-transcriptional processes. [ABSTRACT FROM AUTHOR]

Deep and comprehensive molecular analyses have started to pinpoint the genetic and epigenetic differences between α- and β-cells that could underlie the mechanisms defining their identity. The α-cell transcriptome is altered under different diabetic conditions, resulting in decreased expression of some α-cell-enriched genes alongside increased expression of some β-cell-enriched genes, but without reprogramming into insulin (INS)+ cells or activation of other key β-cell-specific genes. Multiple genetic and chemical methods have been used to reprogram mouse α-cells into INS-secreting cells in vivo , highlighting a difference in plasticity between embryonic and adult α-cells. Human α-cells have also been reprogrammed in vitro using PDX1 plus MAFA overexpression into INS-secreting cells that have reduced immunogenicity. Systematic molecular dissection of the mechanisms controlling α-cell reprogramming using an array of different in vitro and in vivo techniques will be necessary to develop efficient diabetes therapies. β-Cell replacement by in situ reprogramming of non-β-cells is a promising diabetes therapy. Following the observation that near-total β-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity. [ABSTRACT FROM AUTHOR]

Gene regulation and chromosome architecture are intimately linked. Genes with prominent roles in cell identity are often regulated by clusters of enhancer elements. By contrast, a recent study shows housekeeping genes are often regulated through clustering of promoters. We discuss here new regulatory insights for these two types of genes. [ABSTRACT FROM AUTHOR]

The large arrays of cell types in a multicellular organism are defined by their stereotypic size and/or morphology, and, for cells in vivo , by their anatomic positions. Historically, this identity–structure–function correlation was conceptualized as arising from distinct gene expression programs that dictate how cells appear and behave. However, a growing number of studies suggest that a cell's mechanical state is also an important determinant of its identity, both in lineage-committed cells and in pluripotent stem cells. Defining the mechanism by which mechanical inputs influence complex cellular programs remains an area of ongoing investigation. Here, we discuss how the cytoskeleton actively participates in instructing the response of the nucleus and genome to integrate mechanical and biochemical inputs, with a primary focus on the role of the actomyosin–LINC (linker of nucleoskeleton and cytoskeleton) complex axis. Cells can sense intrinsic and extrinsic mechanical inputs through indirect and direct pathways. Linker of nucleoskeleton and cytoskeleton (LINC) complexes are a conduit for direct mechanotransduction. Mechanical state impacts cell identity and fate decisions both in lineage-committed progenitors and pluripotent stem cells. Resetting the cellular mechanical state is a key step in induced pluripotent stem-cell reprogramming. Further developments in tools for robustly measuring intracellular mechanical forces will be critical to advance our understanding of the molecular mechanisms of mechanotransduction. [ABSTRACT FROM AUTHOR]

Beyond its originally discovered role tethering replicated sister chromatids, cohesin has emerged as a master regulator of gene expression. Recent advances in chromatin topology resolution and single-cell studies have revealed that cohesin has a pivotal role regulating highly dynamic chromatin interactions linked to transcription control. The dynamic association of cohesin with chromatin and its capacity to perform loop extrusion contribute to the heterogeneity of chromatin contacts. Additionally, different cohesin subcomplexes, with specific properties and regulation, control gene expression across the cell cycle and during developmental cell commitment. Here, we discuss the most recent literature in the field to highlight the role of cohesin in gene expression regulation during transcriptional shifts and its relationship with human diseases. Analysis of chromatin contacts in single cells and at nucleosome resolution evidence a highly dynamic genome topology. Cohesin is key for genome dynamism because of its capacity to extrude DNA, its dynamic chromatin loading and removal, and the existence of distinct subcomplexes with differential properties and regulation. Stromal antigen 1 and 2 (STAG1 and STAG2)-containing complexes connect cohesin functions in chromosome organization and gene expression regulation in the frame of cell differentiation. Massive cohesin removal and loading as cells transition through mitosis influence gene expression reprogramming across the cell cycle. Cohesin recycling during the telophase/G1 transition might participate in transcription restart and contribute to cell fate determination during development. [ABSTRACT FROM AUTHOR]