Abstract:Key Points
ATAC-seq provides genome-wide chromatin state in 3 cell types of hematopoietic stem/progenitor cells. Transcription factor cohorts are associated with dynamic changes of open chromatin during the differentiation of LT/ST-HSCs to MPPs.
“…Given the transcription-dependent incorporation mode of H3.3 (Ahmad & Henikoff, 2002b, Tagami et al, 2004, it is possible that this biased H3.3 inheritance contributes to or correlates with higher transcriptional activities in GSCs compared to CBs. These results are consistent with previous reports that stem cells maintain an overall more open chromatin state and their differentiated cells begin to "lock down" their chromatin towards a more restricted cell fate (Gaspar-Maia, Alajem et al, 2011, Golkaram, Jang et al, 2017, Turner, 2008, Yu, Wu et al, 2017).…”
Section: Dividing Female Gscs and Cbs Show Globally Symmetric But Locsupporting
Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that produced from a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combined histone labeling with DNA Oligopaints to distinguish old versus new histone distribution and visualize their inheritance patterns at single-gene resolution in asymmetrically dividing cells in vivo. This strategy can be widely applied to other biological contexts involving cell fate establishment during development or tissue homeostasis in multicellular organisms.
“…Given the transcription-dependent incorporation mode of H3.3 (Ahmad & Henikoff, 2002b, Tagami et al, 2004, it is possible that this biased H3.3 inheritance contributes to or correlates with higher transcriptional activities in GSCs compared to CBs. These results are consistent with previous reports that stem cells maintain an overall more open chromatin state and their differentiated cells begin to "lock down" their chromatin towards a more restricted cell fate (Gaspar-Maia, Alajem et al, 2011, Golkaram, Jang et al, 2017, Turner, 2008, Yu, Wu et al, 2017).…”
Section: Dividing Female Gscs and Cbs Show Globally Symmetric But Locsupporting
Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that produced from a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combined histone labeling with DNA Oligopaints to distinguish old versus new histone distribution and visualize their inheritance patterns at single-gene resolution in asymmetrically dividing cells in vivo. This strategy can be widely applied to other biological contexts involving cell fate establishment during development or tissue homeostasis in multicellular organisms.
“…4F ). Apart from an AT-rich motif in both clusters, the cell type-specific cluster 1 peaks were significantly enriched for Elf5 and Runx1 motifs, which are TFs involved in HSC differentiation ( 13 , 34 ). In cluster 2, we found motifs for the known erythroid regulators Gata1 and Arid3a ( 35 , 36 ).…”
Section: Resultsmentioning
confidence: 99%
“…Similarly, long-term HSCs (LT-HSCs) display increased number of assay of transposase accessible chromatin sequencing (ATAC-seq) peaks when compared to short-term HSCs ( 13 ) and high levels of histone H4K16ac ( 14 ), which is known for directly affecting chromatin accessibility in vitro ( 15 ). Nevertheless, several questions remained unanswered: What factors control these global chromatin accessibility changes?…”
Self-renewal and differentiation of hematopoietic stem cells (HSCs) are orchestrated by the combinatorial action of transcription factors and epigenetic regulators. Here, we have explored the mechanism by which histone H4 lysine 16 acetyltransferase MOF regulates erythropoiesis. Single-cell RNA sequencing and chromatin immunoprecipitation sequencing uncovered that MOF influences erythroid trajectory by dynamic recruitment to chromatin and its haploinsufficiency causes accumulation of a transient HSC population. A regulatory network consisting of MOF, RUNX1, and GFI1B is critical for erythroid fate commitment. GFI1B acts as a Mof activator which is necessary and sufficient for cell type-specific induction of Mof expression. Plasticity of Mof-depleted HSCs can be rescued by expression of a downstream effector, Gata1, or by rebalancing acetylation via a histone deacetylase inhibitor. Accurate timing and dosage of Mof expression act as a rheostat for the feedforward transcription factor network that safeguards progression along the erythroid fate.
“…One such study, carried out in human T-helper cells, found that genes with accessible promoters and high expression were enriched for housekeeping functions, whereas those with inaccessible promoters were enriched for olfactory terms [27]. A more recent study also found that genes with accessible promoters in three different types of hematopoietic stem cells (HSCs) were enriched for terms related to regulating the cell cycle and DNA damage and repair [28]. Fig.…”
Background
The assay for transposase-accessible chromatin (ATAC-seq) is a powerful method to examine chromatin accessibility. While many studies have reported a positive correlation between gene expression and promoter accessibility, few have investigated the genes that deviate from this trend. In this study, we aimed to understand the relationship between gene expression and promoter accessibility in multiple cell types while also identifying gene regulatory networks in the placenta, an understudied organ that is critical for a successful pregnancy.
Results
We started by assaying the open chromatin landscape in the mid-gestation placenta, when the fetal vasculature has started developing. After incorporating transcriptomic data generated in the placenta at the same time point, we grouped genes based on their expression levels and ATAC-seq promoter coverage. We found that the genes with the strongest correlation (high expression and high coverage) are likely involved in housekeeping functions, whereas tissue-specific genes were highly expressed and had only medium–low coverage. We also predicted that genes with medium–low expression and high promoter coverage were actively repressed. Within this group, we extracted a protein–protein interaction network enriched for neuronal functions, likely preventing the cells from adopting a neuronal fate. We further confirmed that a repressive histone mark is bound to the promoters of genes in this network. Finally, we ran our pipeline using ATAC-seq and RNA-seq data generated in ten additional cell types. We again found that genes with the strongest correlation are enriched for housekeeping functions and that genes with medium–low promoter coverage and high expression are more likely to be tissue-specific. These results demonstrate that only two data types, both of which require relatively low starting material to generate and are becoming more commonly available, can be integrated to understand multiple aspects of gene regulation.
Conclusions
Within the placenta, we identified an active placenta-specific gene network as well as a repressed neuronal network. Beyond the placenta, we demonstrate that ATAC-seq data and RNA-seq data can be integrated to identify tissue-specific genes and actively repressed gene networks in multiple cell types.
Electronic supplementary material
The online version of this article (10.1186/s13072-019-0260-2) contains supplementary material, which is available to authorized users.
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