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CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo.

ABSTRACT: During development eukaryotic gene expression is coordinated by dynamic changes in chromatin structure. Measurements of accessible chromatin are used extensively to identify genomic regulatory elements. Whilst chromatin landscapes of pluripotent stem cells are well characterised, chromatin accessibility changes in the development of somatic lineages are not well defined. Here we show that cell-specific chromatin accessibility data can be produced via ectopic expression of E. coli Dam methylase in vivo, without the requirement for cell-sorting (CATaDa). We have profiled chromatin accessibility in individual cell-types of Drosophila neural and midgut lineages. Functional cell-type-specific enhancers were identified, as well as novel motifs enriched at different stages of development. Finally, we show global changes in the accessibility of chromatin between stem-cells and their differentiated progeny. Our results demonstrate the dynamic nature of chromatin accessibility in somatic tissues during stem cell differentiation and provide a novel approach to understanding gene regulatory mechanisms underlying development.

SUBMITTER: Aughey GN

PROVIDER: S-EPMC5826290 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo.

Aughey Gabriel N GN Estacio Gomez Alicia A Thomson Jamie J Yin Hang H Southall Tony D TD

eLife 20180226

During development eukaryotic gene expression is coordinated by dynamic changes in chromatin structure. Measurements of accessible chromatin are used extensively to identify genomic regulatory elements. Whilst chromatin landscapes of pluripotent stem cells are well characterised, chromatin accessibility changes in the development of somatic lineages are not well defined. Here we show that cell-specific chromatin accessibility data can be produced via ectopic expression of <i>E. coli</i> Dam meth ...[more]

PMID: 29481322

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Project description:Tissue differentiation is accompanied by genome-wide changes in the underlying chromatin structure and dynamics, or epigenome. By controlling when, where, and what regulatory factors have access to the underlying genomic DNA, the epigenome influences the cell's transcriptome and ultimately its function. Existing genomic methods for analyzing cell-type-specific changes in chromatin generally involve two elements: (i) a source for purified cells (or nuclei) of distinct types, and (ii) a specific treatment that partitions or degrades chromatin by activity or structural features. For many cell types of great interest, such assays are limited by our inability to isolate the relevant cell populations in an organism or complex tissue containing an intertwined mixture of other cells. This limitation has confined available knowledge of chromatin dynamics to a narrow range of biological systems (cell types that can be sorted/separated/dissected in large numbers and tissue culture models) or to amalgamations of diverse cell types (tissue chunks, whole organisms).Transgene-driven expression of DNA/chromatin modifying enzymes provides one opportunity to query chromatin structures in expression-defined cell subsets. In this work we combine in vivo expression of a bacterial DNA adenine methyltransferase (DAM) with high throughput sequencing to sample tissue-specific chromatin accessibility on a genome-wide scale. We have applied the method (DALEC: Direct Asymmetric Ligation End Capture) towards mapping a cell-type-specific view of genome accessibility as a function of differentiated state. Taking advantage of C. elegans strains expressing the DAM enzyme in diverse tissues (body wall muscle, gut, and hypodermis), our efforts yield a genome-wide dataset measuring chromatin accessibility at each of 538,000 DAM target sites in the C. elegans (diploid) genome.Validating the DALEC mapping results, we observe a strong association between observed coverage by nucleosomes and low DAM accessibility. Strikingly, we observed no extended regions of inaccessible chromatin for any of the tissues examined. These results are consistent with "local choreography" models in which differential gene expression is driven by intricate local rearrangements of chromatin structure rather than gross impenetrability of large chromosomal regions.

Dataset Information

CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo.

Publications

CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo.

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