Abstract 1090: NR2F1 coordinates a dormancy program by inducing low self-renewal capacity and a repressive chromatin state.

The transcriptional repressors Polycomb repressive complex 1 (PRC1) and PRC2 are required to maintain cell fate during embryonic development. PRC1 and PRC2 catalyze distinct histone modifications, establishing repressive chromatin at shared targets. How PRC1, which consists of canonical PRC1 (cPRC1) and variant PRC1 (vPRC1) complexes, and PRC2 cooperate to silence genes and support mouse embryonic stem cell (mESC) self-renewal is unclear. Using combinatorial genetic perturbations, we show that independent pathways of cPRC1 and vPRC1 are responsible for maintenance of H2A monoubiquitylation and silencing of shared target genes. Individual loss of PRC2-dependent cPRC1 or PRC2-independent vPRC1 disrupts only one pathway and does not impair mESC self-renewal capacity. However, loss of both pathways leads to mESC differentiation and activation of a subset of lineage-specific genes co-occupied by relatively high levels of PRC1/PRC2. Thus, parallel pathways explain the differential requirements for PRC1 and PRC2 and provide robust silencing of lineage-specific genes.

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Chromatin state barriers enforce an irreversible mammalian cell fate decision

10.1101/2021.05.12.443709 ◽

2021 ◽

Author(s):

Mario Andres Blanco ◽

David Sykes ◽

Lei Gu ◽

Mengjun Wu ◽

Ricardo Petroni ◽

...

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Chromatin State ◽

Self Renewal ◽

Transcription Factor Activation ◽

Point Of No Return ◽

Myeloid Development ◽

Stem And Progenitor Cells ◽

Site Access ◽

Fate Decision

Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogated determinants of this "point of no return" in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how chromatin state enforces and perpetuates cell fate and identifies potential avenues for manipulating cell identity.

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Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons

Cell Reports ◽

10.1016/j.celrep.2016.08.028 ◽

2016 ◽

Vol 16 (11) ◽

pp. 2889-2900 ◽

Cited By ~ 24

Author(s):

Ernest Palomer ◽

Adrián Martín-Segura ◽

Shishir Baliyan ◽

Tariq Ahmed ◽

Detlef Balschun ◽

...

Keyword(s):

Hippocampal Neurons ◽

Chromatin State ◽

Repressive Chromatin

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Structural Analysis of the Arabidopsis AL2-PAL and PRC1 Complex Provides Mechanistic Insight into Active-to-Repressive Chromatin State Switch

Journal of Molecular Biology ◽

10.1016/j.jmb.2018.08.021 ◽

2018 ◽

Vol 430 (21) ◽

pp. 4245-4259 ◽

Cited By ~ 5

Author(s):

Ling Peng ◽

Longlong Wang ◽

Yingpei Zhang ◽

Aiwu Dong ◽

Wen-Hui Shen ◽

...

Keyword(s):

Structural Analysis ◽

Chromatin State ◽

Repressive Chromatin ◽

Mechanistic Insight ◽

Insight Into

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Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin

10.1101/2021.02.03.429504 ◽

2021 ◽

Author(s):

Wei Zhao ◽

Lingxia Qiao ◽

Shiyu Yan ◽

Qing Nie ◽

Lei Zhang

Keyword(s):

Cell Fate ◽

Histone Modifications ◽

Necessary Conditions ◽

Chromatin State ◽

Chromatin Domain ◽

Biological Processes ◽

Cell Fate Determination ◽

Repressive Chromatin ◽

And Function ◽

Bivalent Chromatin Domain

AbstractBivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the experimental data from a recent study. Investigation of the composition of bivalent chromatin reveals that bivalent nucleosomes carrying both H3K4me3 and H3K27me3 account for no more than half of nucleosomes at the bivalent chromatin domain. We identify that bivalent chromatin not only allows transitions to multiple states but also serves as a stepping stone to facilitate a step-wise transition between repressive chromatin state and activating chromatin state, and thus elucidate crucial roles of bivalent chromatin in mediating phenotypical plasticity during cell fate determination.

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