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Histone H3K4me3 signal breadth reveals constitutive and hypoxia stress responsive endometrial functions linked to endometriosis

ABSTRACT: We report sequening of chromatin immunoprecipitated DNA (ChIP-Seq) of histone H3 at lysine 4 (H3K4me3) normoxic and hypoxia treated endometrial stromal fibroblasts (ESF) and hypoxia treated differentiated decidual stromal cells (DSC),

ORGANISM(S): Homo sapiens

PROVIDER: GSE167946 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:Herein, we investigated eMSC and eSF freshly isolated from endometrium from women with and without endometriosis and compared them to their respective short- and long-term cultures and subsequent decidualization response to progesterone. ABSTRACT Human endometrium undergoes cyclic tissue shedding with ensuing regeneration involving stem/progenitor cells, but the role of multipotent resident endometrial mesenchymal stem cells (eMSC) as progenitors of the endometrial stromal fibroblast (eSF) has not been definitively demonstrated. Progesterone (P4)-driven differentiation (decidualization) of eSF is abnormal in endometriosis, displaying P4-resistance in vivo and in vitro. This study investigated whether eMSC are precursors of eSF and, if so, whether the endometriosis P4-resistant phenotype is inherited from eMSC progenitors or acquired by eSF lineage cells within the endometrial niche. To this end we analyzed the transcriptomes of eMSC and eSF isolated by fluorescence activated cell sorting (FACS) from eutopic endometrium of women with (eMSCFACS.endo, eSFFACS.endo) and without (eMSCFACS.control, eSFFACS.control) endometriosis, and of primary cultures derived from these sorted populations. FACS-isolated eMSC and eSF displayed distinct sets of differentially expressed lineage-associated genes (LG) with >95% of the 200 most highly expressed LG conserved in endometriosis. eSFcontrol in culture maintained in vitro expression of 45% eSF LG; whereas eSFendo displayed less in vitro LG stability, expressing 33% eSF LG. Under the same culture conditions, eMSCcontrol underwent in vitro eSF lineage differentiation (eMSC→eSFcontrol), progressively losing stemness (down-regulated 81% eMSC LG) and acquiring an in vitro eSFcontrol phenotype (up-regulated 55% eSF LG) with minimal transcriptome differences vs. eSFcontrol cultures (19 genes all <2 fold change). Likewise eMSCendo cultures underwent in vitro eSF lineage differentiation (eMSC→eSFendo), down-regulating 77% eMSC LG and up-regulating 50% eSF LG, and there were 78 differentially expressed genes (-2.73 to +2.81 fold change) in eMSC→eSFendo vs. eSFendo. The in vitro disease phenotypes of eSFendo and eMSC→eSFendo shared 49 common genes differentially expressed vs. their control counterparts. However, 78 and 89 genes, respectively, were unique to eSFendo and eMSC→eSFendo, and pathway analysis revealed a proinflammatory phenotype in eSFendo but not eMSC→eSFendo cultures, suggesting divergent niche effects for in vivo vs. in vitro lineage differentiation. Cultures of eSFcontrol and eMSC→eSFcontrol responded to P4 with IGFBP1 secretion, while eSFendo and eMSC→eSFendo cultures did not, demonstrating P4-resistance inherited from eMSCendo. These findings substantiate eMSC as progenitors of eSF and reveal novel aspects of the eSF disease phenotype in endometriosis with P4-resistance inherited from the eMSC and a proinflammatory component acquired by the eSF lineage within the endometrial niche.

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Histone H3K4me3 signal breadth reveals constitutive and hypoxia stress responsive endometrial functions linked to endometriosis

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