Organisms require an appropriate balance of stability and reversibility in gene expression programmes to maintain cell identity or to enable responses to stimuli; epigenetic regulation is integral to this dynamic control. Post-translational modification of histones by methylation is an important and widespread type of chromatin modification that is known to influence biological processes in the context of development and cellular responses. To evaluate how histone methylation contributes to stable or reversible control, we provide a broad overview of how histone methylation is regulated and leads to biological outcomes. The importance of appropriately maintaining or reprogramming histone methylation is illustrated by its links to disease and ageing and possibly to transmission of traits across generations.

/pdf/histone-methylation-a-dynamic-mark-in-health-disease-and-53e9mgdnmh.pdf

Histone methylation: a dynamic mark in health, disease and inheritance

Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair Genomic techniques based on chromosome conformation capture (3C) assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei Here we introduce single-cell Hi-C, combined with genome-wide statistical analysis and structural modelling of single-copy X chromosomes, to show that individual chromosomes maintain domain organization at the megabase scale, but show variable cell-to-cell chromosome structures at larger scales Despite this structural stochasticity, localization of active gene domains to boundaries of chromosome territories is a hallmark of chromosomal conformation Single-cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organization underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns

Single-cell Hi-C reveals cell-to-cell variability in chromosome structure

How DNA is organized in three dimensions inside the cell nucleus and how that affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic, and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C) the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction datasets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyze chromatin interaction data.

/pdf/exploring-the-three-dimensional-organization-of-genomes-36n1pxvxrk.pdf

Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data

Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.

/pdf/transgenerational-epigenetic-inheritance-of-longevity-in-yfpys4s76k.pdf

Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans

Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a near-universal chromatin modification at the transcription start site of active genes in eukaryotes from yeast to man and its levels reflect the amount of transcription. Because of this association, H3K4me3 is often described as an 'activating' histone modification and assumed to have an instructive role in the transcription of genes, but the field is lacking a conserved mechanism to support this view. The overwhelming finding from genome-wide studies is that actually very little transcription changes upon removal of most H3K4me3 under steady-state or dynamically changing conditions, including at mammalian CpG island promoters. Instead, rather than a major role in instructing transcription, time-resolved experiments provide more evidence supporting the deposition of H3K4me3 into chromatin as a result of transcription, influencing processes such as memory of previous states, transcriptional consistency between cells in a population and transcription termination.

/pdf/is-h3k4me3-instructive-for-transcription-activation-tw6bnu81j8.pdf

Is H3K4me3 instructive for transcription activation

https://www.cell.com/current-biology/pdf/S0960-9822(10)00054-0.pdf

Methylation of H3K4 Is Required for Inheritance of Active Transcriptional States

Despite the distinctive structure of mitotic chromosomes, it has not been possible to visualise individual chromosomes in living interphase cells, where chromosomes spend over 90% of their time. Studies of interphase chromosome structure and dynamics use fluorescence in-situ hybridisation (FISH) on fixed cells, which potentially damages structure and loses dynamic information. We have developed a new methodology, involving photoactivation of labelled histone H3 at mitosis, to visualise individual and specific human chromosomes in living interphase cells. Our data revealed bulk chromosome volume and morphology are established rapidly after mitosis, changing only incrementally after the first hour of G1. This contrasted with the behaviour of specific loci on labelled chromosomes, which showed more progressive reorganisation, and revealed that “looping out” of chromatin from chromosome territories is a dynamic state. We measured considerable heterogeneity in chromosome decondensation, even between sister chromatids, which may reflect local structural impediments to decondensation and could potentially amplify transcriptional noise. Chromosome structure showed tremendous resistance to inhibitors of transcription, histone deacetylation and chromatin remodelling. Together, these data indicate steric constraints determine structure, rather than innate chromosome architecture or function-driven anchoring, with interphase chromatin organisation governed primarily by opposition between needs for decondensation and the space available for this to happen.

/pdf/stable-morphology-but-dynamic-internal-reorganisation-of-3yabla7up5.pdf

Stable Morphology, but Dynamic Internal Reorganisation, of Interphase Human Chromosomes in Living Cells

Stimulation of transcription by extracellular signals is a major component of a cell's decision making. Yet the quantitative relationship between signal and acute transcriptional response is unclear. One view is that transcription is directly graded with inducer concentration. In an alternative model, the response occurs only above a threshold inducer concentration. Standard methods for monitoring transcription lack continuous information from individual cells or mask immediate-early transcription by measuring downstream protein expression. We have therefore used a technique for directly monitoring nascent RNA in living cells, to quantify the direct transcriptional response to an extracellular signal in real time, in single cells. At increasing doses of inducer, increasing numbers of cells displayed a transcriptional response. However, over the same range of doses, the change in cell response strength, measured as the length, frequency and intensity of transcriptional pulses, was small, with considerable variation between cells. These data support a model in which cells have different sensitivities to developmental inducer and respond in a digital manner above individual stimulus thresholds. Biased digital responses may be necessary for certain forms of developmental specification. Limiting bias in responsiveness is required to reduce noise in positional signalling.

Digital nature of the immediate-early transcriptional response

https://doi.org/10.1016/j.ynstr.2022.100474

Choosing memory retrieval strategies: A critical role for inhibition in the dentate gyrus

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Methylation of H3K4 Is Required for Inheritance of Active Transcriptional States

Stable Morphology, but Dynamic Internal Reorganisation, of Interphase Human Chromosomes in Living Cells

Digital nature of the immediate-early transcriptional response

Choosing memory retrieval strategies: A critical role for inhibition in the dentate gyrus