Dataset Information

A Critical Role for Estrogen-Related Receptor Signaling in Cardiac Maturation.

ABSTRACT:

Rationale

The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell-derived cardiac myocytes.

Objective

To delineate transcriptional drivers of cardiac maturation.

Methods and results

We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures.

Conclusions

ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.

SUBMITTER: Sakamoto T

PROVIDER: S-EPMC7274895 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Breast cancer (BC) is highly heterogeneous with ~?60-70% of estrogen receptor positive BC patient's response to anti-hormone therapy. Estrogen receptors (ERs) play an important role in breast cancer progression and treatment. Estrogen related receptors (ERRs) are a group of nuclear receptors which belong to orphan nuclear receptors, which have sequence homology with ERs and share target genes. Here, we investigated the possible role and clinicopathological importance of ERR? in breast cancer. METHODS:Estrogen related receptor ? (ERR?) expression was examined using tissue microarray slides (TMA) of Breast Carcinoma patients with adjacent normal by immunohistochemistry and in breast cancer cell lines. In order to investigate whether ERR? is a direct target of ER?, we investigated the expression of ERR? in short hairpin ribonucleic acid knockdown of ER? breast cancer cells by western blot, qRT-PCR and RT-PCR. We further confirmed the binding of ER? by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), Re-ChIP and luciferase assays. Fluorescence-activated cell sorting analysis (FACS) was performed to elucidate the role of ERR? in cell cycle regulation. A Kaplan-Meier Survival analysis of GEO dataset was performed to correlate the expression of ERR? with survival in breast cancer patients. RESULTS:Tissue microarray (TMA) analysis showed that ERR? is significantly down-regulated in breast carcinoma tissue samples compared to adjacent normal. ER?+?ve breast tumors and cell lines showed a significant expression of ERR? compared to ER-ve tumors and cell lines. Estrogen treatment significantly induced the expression of ERR? and it was ER? dependent. Mechanistic analyses indicate that ER? directly targets ERR? through estrogen response element and ERR? also mediates cell cycle regulation through p18, p21cip and cyclin D1 in breast cancer cells. Our results also showed the up-regulation of ERR? promoter activity in ectopically co-expressed ER? and ERR? breast cancer cell lines. Fluorescence-activated cell sorting analysis (FACS) showed increased G0/G1 phase cell population in ERR? overexpressed MCF7 cells. Furthermore, ERR? expression was inversely correlated with overall survival in breast cancer. Collectively our results suggest cell cycle and tumor suppressor role of ERR? in breast cancer cells which provide a potential avenue to target ERR? signaling pathway in breast cancer. CONCLUSION:Our results indicate that ERR? is a negative regulator of cell cycle and a possible tumor suppressor in breast cancer. ERR? could be therapeutic target for the treatment of breast cancer.