Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation

Abstract

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

“…Consistent with a role for cohesin in shaping gene regulatory architecture, its depletion prevents adequate activation of inducible genes (Cuartero et al, 2018). Surprisingly however, steady-state gene expression levels are less affected upon architectural protein depletion (Busslinger et al, 2017;Haarhuis et al, 2017;Nora et al, 2017;Rao et al, 2017;Schwarzer et al, 2017;Seitan et al, 2013;Sofueva et al, 2013).…”

“…However, the fact that many interactions with active enhancers are retained upon architectural protein depletion, and only a small number of contacts are gained in these conditions, may explain why this perturbation does not have a more pronounced effect on steady-state transcription. How can these observations be reconciled with the requirement for cohesin for gene induction (Cuartero et al, 2018) and lineagespecific gene regulation (Liu et al, 2019)? One possibility is that in non-transcriptionally-permissive chromatin contexts, cohesin/CTCF-independent promoter contacts are unable to form in the absence of some prior activation events, such as chromatin decompaction of the locus or establishment of appropriate chromosomal conformation.…”

Chromosome organization by one-sided and two-sided loop extrusion

“…Additionally, the loss of interphase chromosome structure in vertebrates by loss of cohesin SMC complexes can affect gene expression ( e.g. , (Bompadre and Andrey, 2019;Cuartero et al, 2018;Delaneau et al, 2019;Lupiáñez et al, 2015;Merkenschlager and Nora, 2016;Nora et al, 2017;Rao et al, 2017;Schoenfelder and Fraser, 2019;Schwarzer et al, 2017;Seitan et al, 2013) ). Similarly, mutations that perturb cohesin or condensin can lead to human developmental / disorders, such as Cornelia de Lange syndrome (de Lange, 1933) and microcephaly (Martin et al, 2016) .…”

Systematic identification of factors bound to isolated metaphase ESC chromosomes reveals a role for chromatin repressors in compaction

“…To test this, we asked whether experimental cleavage of cohesin could significantly alter the structure of isolated chromosomes. Cohesin complexes are composed of Smc1, Smc3, the kleisin Scc1, and one of three auxillary subunits 13 and are required to keep sister chromatids together from DNA replication until mitosis, as well having roles in interphase genome organisation, gene transcription and DNA repair [12][13][14][15][16][17] . Proteomic analysis (Figure 1i and S1c) indicate that components of the cohesin complex bind mitotic chromosomes in different cell types 25,55,56 and are dynamically regulated so that the majority of cohesin dissociates from chromosome arms during prophase.…”

“…While these interactions differ from those at interphase, it seems likely that at least some factors mediating local chromatin condensation during interphase might have similar or related roles in mitosis. The cohesin complex, for example, is required to keep newly replicated sister chromatids in close physical proximity during S/G2 to M phases of the cell cycle, but can also modulate interphase gene expression through local enhancer-promoter contact [12][13][14][15][16][17] .…”