Epigenetic regulation of embryonic stem cells by ATP-dependent BAF chromatin remodeling complexes

ATP依赖性BAF染色质重塑复合物对胚胎干细胞的表观遗传调控

• 批准号: 10226169
• 负责人: Diana Clare Hargreaves
• 金额: $ 48.1万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226169
• 关键词: Affect; Binding; Biochemical; Bromodomain; Cells; Chromatin; Chromatin Remodeling Factor; Complex; DNA Sequence Alteration; Derivation procedure; Development; Disease; Disease model; Embryo; Epigenetic Process; Exhibits; Gene Expression Regulation; Gene Family; Generations; Genetic Transcription; Genome; Genomics; Goals; Growth; Heterogeneity; Histones; In Vitro; Individual; Injury; Inner Cell Mass; Knowledge; Lysine; Mediating; Natural regeneration; Organism; Property; Proteins; Reader; Regenerative Medicine; Regulator Genes; Research; Role; Tissues; Transcriptional Regulation; cell type; chromatin remodeling; combinatorial; embryonic stem cell; epigenetic regulation; in vivo; novel; pluripotency; prevent; programs; self-renewal; stem cell genes; stem cell self renewal; stem cells; transcription factor

PROJECT SUMMARY Self-renewal and pluripotency are defining properties of an embryonic stem cell (ESC). Although extremely transient in vivo, these cells can be captured from the inner cell mass of the embryo and maintained indefinitely in a pluripotent state or differentiated into essentially any specialized cell in vitro. As such, embryonic stem cells (ESCs) hold great promise for regenerative medicine, which seeks to use ESCs to regenerate or rejuvenate cells and tissues that have been damaged due to injury, disease, or underlying genetic mutations. However, to leverage their full potential, we must understand the mechanisms that control ESC self-renewal and pluriptency to allow (re)generation of any tissue while preventing aberrant growth or depletion of the stem cell pool. Stem cell identity is defined by a gene regulatory network dictated by the master regulators OCT4, SOX2 and NANOG. However, the binding of these transcriptional factors is in turn highly dependent on the accessibility of the chromatin landscape. To access the underlying genomic information, histone proteins must be repositioned or removed, a function that is performed by ATP-dependent chromatin remodeling complexes. In particular, several components of the mammalian SWI/SNF or BAF complex are essential for formation of the inner cell mass and for derivation of ESCs in vitro. BAF complexes are regulated by the combinatorial assembly of homologous subunits from gene families. However, there is currently no mechanistic understanding of how unique combinations of distinct subunits affect BAF complex targeting or function. Using biochemical approaches, a completely novel and previously undescribed form of the BAF complex was discovered in ESCs that contains the acetyl lysine reader, Bromodomain-containing protein 9 (BRD9). Due to the incorporation of BRD9 and other unique subunits, the BRD9-containing BAF complex or 'BBAF complex' is uniquely targeted across the genome and exhibits specific regulatory interactions not found associated with canonical BAF complexes. Moreover, the BBAF complex lacks certain subunits that are critical for ATP- dependent chromatin remodeling, suggesting that it may have alternate function. The goals for the next five years are to determine the mechanism of BRD9-mediated chromatin targeting of the BBAF complex and how that relates to the transcriptional regulation of genes involved in ESC self-renewal and pluripotency. These studies will aid in our understanding of how BAF complex heterogeneity contributes to the precise control of the ESC transcriptional program and provide a framework for understanding the roles of individual BAF subunits in contributing to cell type- and developmental stage-specific function of BAF complexes.

项目总结