Heterogeneous enhancer states orchestrate β cell responses to metabolic stress
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ABSTRACT:
PROVIDER: PRJNA1009030 | ENA |
REPOSITORIES: ENA
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Project description:Obesity-induced β cell dysfunction is a significant contributor to the onset of type 2 diabetes. Metabolic stress triggers expansive enhancer and gene expression dynamics in islet endocrine cells. However, identifying the precise gene regulatory network and the corresponding epigenetic mechanisms driving the islet dysfunction remains challenging. Here we utilize Paired-Tag, a combinatorial index-based multi-omic platform, to concurrently profile single-nuclei RNA with H3K4me1 or H3K27ac, two distinct histone modifications defining enhancer states, in lean and obese islets. Our study revealed gene expression, distinct enhancer states, RNA-enhancer links, and intra-islet paracrine communications that align with amplified unfolded protein responses and decreased insulin secretion function at a single-cell level.
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Project description:Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are pre-marked by H3K4me1 in multipotent progenitors. However, H3K4me1 levels at a subset of enhancers are elevated during developmental progression, resulting in evolving enhancer repertoires that we propose orchestrate the myeloid and B cell fates. ChIP-Seq and gene expression profiling were performed in an inducible hematopoietic pluripotent cell line that can be differentiated into multiple lymphoid lineages. This submission contains ChIP-Seq data. Recent studies have demonstrated a tight correlation between transcriptionally active promoters and H3K4 trimethylation, whereas H3K4 monomethylation has been associated with enhancer activity. To determine whether the changes in gene expression patterns upon differentiation correlate with the presence of H3K4me3 as well as H3K4me1, ChIP-sequencing was performed on these two marks on cell lysates that were derived from Id2-HPCs and differentiated Id2-HPCs. The H3K4me1 marks were further analyzed to investigate the dynamics of enhancer repertoires between these cells. Id2-HPCs were cultured in IMDM medium supplemented with 10% FCS/2% PSG/M-NM-2-me and IL7, Flt3-ligand, and SCF cytokines on S17 feeder cells in a humidified incubator at 37 degrees C with 5% CO2. Id2-HPC expanded cells were depleted of small (<1-5%) numbers of CD19-, CD25- and CD11b-positive cells by auto-MACS. For myeloid differentiation, cells were cultured for up to 6 days in IMDM medium supplemented with 10% FCS/2% PSG/M-NM-2-me and IL3, Flt3L, GMCSF and MCSF cytokines. To promote B-cell differentiation, cells were cultured for up to 5 days in IMDM medium supplemented with 10% FCS/2% PSG/M-NM-2-me and IL-7 and SCF cytokines on S17 feeder cells in the presence of 1 ug/mL doxycycline, or alternatively, in alpha-MEM medium in the presence of cytokines and on Tst-4 stromal cells.
2011-09-01 | E-GEOD-30858 | biostudies-arrayexpress
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Project description:Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are pre-marked by H3K4me1 in multipotent progenitors. However, H3K4me1 levels at a subset of enhancers are elevated during developmental progression, resulting in evolving enhancer repertoires that we propose orchestrate the myeloid and B cell fates. ChIP-Seq and gene expression profiling were performed in an inducible hematopoietic pluripotent cell line that can be differentiated into multiple lymphoid lineages. This submission contains gene expression profiling data. To characterize Id2-HPCs, we performed microarray analysis using RNA derived from cultured E2A-deficient cells, EBF-deficient cells and Id2-HPCs. Id2-HPC cells were cultured in IMDM medium supplemented with 10% FCS/2% PSG/β-me and IL7, Flt3-ligand, and SCF cytokines on S17 feeder cells in a humidified incubator at 37 degrees C with 5% CO2. Id2-HPC expanded cells were depleted of small (<1-5%) numbers of CD19-, CD25- and CD11b-positive cells by auto-MACS. E2A -/- and EBF -/- cells were cultured in IMDM supplemented with 10% FCS/2% PSG/β-me on S17 feeder cells in the presence of IL-7, Flt3-ligand, and SCF cytokines in a humidified incubator at 37 degree C with 5% CO2.
2011-08-31 | E-GEOD-30855 | biostudies-arrayexpress
Project description:Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are pre-marked by H3K4me1 in multipotent progenitors. However, H3K4me1 levels at a subset of enhancers are elevated during developmental progression, resulting in evolving enhancer repertoires that we propose orchestrate the myeloid and B cell fates.
2011-09-01 | GSE30858 | GEO
Project description:Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are pre-marked by H3K4me1 in multipotent progenitors. However, H3K4me1 levels at a subset of enhancers are elevated during developmental progression, resulting in evolving enhancer repertoires that we propose orchestrate the myeloid and B cell fates.
2011-09-01 | GSE30855 | GEO