Bookmarking by “non-pioneer” transcription factors during liver development establishes competence for future gene activation
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ABSTRACT:
PROVIDER: PRJNA564498 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10084400.fastq.gz | Fastqsanger.gz | |||
| SRR10084401.fastq.gz | Fastqsanger.gz | |||
| SRR10084402.fastq.gz | Fastqsanger.gz | |||
| SRR10084403.fastq.gz | Fastqsanger.gz | |||
| SRR10084404.fastq.gz | Fastqsanger.gz |
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Project description:Transcription factor binding to enhancer and promoter regions is critical for gene activation. To understand how cell-specific gene expression patterns are generated, we studied the developmental timing of association of two prominent hepatic transcription factors with gene regulatory regions. We found that most individual binding events displayed extraordinarily high temporal variations during liver development. Early and persistent binding is necessary but not sufficient for gene activation. Stable gene expression patterns are mainly generated by the combinatorial activity of multiple transcription factors, which mark regulatory regions long before activation and promote progressive broadening of active chromatin domains. Both, temporally stable and dynamic binding events contribute to the developmental maturation of active promoter configurations. The results reveal a developmental “bookmarking” function of transcription factors, and illuminate remarkable parallels between the principles employed for gene activation during development, evolution and upon mitotic exit.
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Project description:Transcription factor binding to enhancer and promoter regions critical for homeostatic adult gene activation is established during development. To understand how cell-specific gene expression patterns are generated, we study the developmental timing of association of two prominent hepatic transcription factors with gene regulatory regions. Most individual binding events display extraordinarily high temporal variations during liver development. Early and persistent binding is necessary, but not sufficient, for gene activation. Stable gene expression patterns are the result of combinatorial activity of multiple transcription factors, which mark regulatory regions long before activation and promote progressive broadening of active chromatin domains. Both temporally stable and dynamic, short-lived binding events contribute to the developmental maturation of active promoter configurations. The results reveal a developmental bookmarking function of master regulators and illuminate remarkable parallels between the principles employed for gene activation during development, during evolution, and upon mitotic exit.
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Project description:To maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is thought to be mediated, in part, by mitotic bookmarking by transcription factors (TF). However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses of Drosophila early embryos, we provide evidence that the pioneer-like transcription factor GAF acts as stable mitotic bookmarker during zygotic genome activation. We report that GAF remains associated to a large fraction of its interphase targets (37%). Mitotically-bound loci include cis-regulatory sequences of key developmental genes, with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and a subset is also mitotically bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we provide evidence that GAF binding establishes competence for rapid activation upon mitotic exit.
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Project description:Establishing cell type–specific chromatin landscapes is essential for cellular identity, yet how these landscapes are generated and maintained remains poorly understood. Here, we demonstrate that the chromatin remodeler SMARCA5 facilitates epigenetic priming required for retinoic acid–induced differentiation in the male germline. Germ cell–specific deletion of Smarca5 results in a complete loss of differentiating spermatogonia, phenocopying vitamin A–deficient mice lacking retinoic acid signaling. During the perinatal transition from prospermatogonia to undifferentiated spermatogonia, SMARCA5 is recruited to DMRT1-binding sites located at distal putative enhancers and promoters of germline genes. The SMARCA5–DMRT1 pioneer complex establishes chromatin accessibility at these loci, generating poised enhancers and promoters that serve as retinoic acid receptor (RAR)–binding sites. Thus, SMARCA5 licenses transcriptional responses to retinoic acid that enable spermatogenic differentiation. Our findings uncover a critical epigenetic priming mechanism that links pioneer factor activity to external signal responsiveness in the germline.
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Project description:Mitotic bookmarking transcription factors (TFs) are thought to mediate rapid and accurate post-mitotic gene reactivation. However, the loss of individual bookmarking TFs often leads to the deregulation of only a small proportion of their mitotic targets, raising doubts on the significance and importance of their bookmarking function. Here, we used targeted proteomics of the mitotic bookmarking TF ESRRB, an orphan nuclear receptor, to discover an unexpected redundancy among members of the protein superfamily of nuclear receptors. Focusing on the nuclear receptor NR5A2, which together with ESRRB is essential in maintaining pluripotency in mouse embryonic stem cells, we demonstrate conjoint bookmarking activity of both factors on promoters and enhancers of a large fraction of active genes, particularly the most rapidly and strongly reactivated ones. Upon fast and simultaneous degradation of both factors during mitotic exit, hundreds of mitotic targets of ESRRB/NR5A2, including key players of the pluripotency network, display attenuated transcriptional reactivation. We propose that redundancy in mitotic bookmarking TFs, especially nuclear receptors, confers robustness to the reestablishment of gene regulatory networks after mitosis.
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