Alternatively Constructed Estrogen Receptor Alpha-Driven Super-Enhancers Result in Similar Gene Expression in Breast and Endometrial Cell Lines

Bojcsuk, Dóra; Nagy, Gergely; Bálint, Bálint László

doi:10.3390/ijms21051630

Cited by 2 publications

(1 citation statement)

References 65 publications

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“…According to these results, BMDM- and/or B cell-specific regions both show PU.1 and RUNX motif enrichments (purple), BMDM- and/or iWAT-specific regions both have C/EBP and AP-1 (TRE) motifs enriched (red), and CRE and enhancer (E)-box motifs (black) enriched the most in macrophages ( Supplementary Figure S1A ). These results confirm that the cistrome of a certain LDTF can be diverse in different cell types, largely affected by the actual collaborating TFs ( 60 , 61 ). In addition, the macrophage-specific motif hits suggest the possible roles of multiple bZIP and—the E-box binding—bHLH proteins besides the well-known LDTFs.…”

Section: Resultssupporting

confidence: 72%

Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression

Nagy,

Bojcsuk,

Tzerpos

et al. 2024

Nucleic Acids Research

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Mammalian promoters consist of multifarious elements, which make them unique and support the selection of the proper transcript variants required under diverse conditions in distinct cell types. However, their direct DNA-transcription factor (TF) interactions are mostly unidentified. Murine bone marrow-derived macrophages (BMDMs) are a widely used model for studying gene expression regulation. Thus, this model serves as a rich source of various next-generation sequencing data sets, including a large number of TF cistromes. By processing and integrating the available cistromic, epigenomic and transcriptomic data from BMDMs, we characterized the macrophage-specific direct DNA-TF interactions, with a particular emphasis on those specific for promoters. Whilst active promoters are enriched for certain types of typically methylatable elements, more than half of them contain non-methylatable and prototypically promoter-distal elements. In addition, circa 14% of promoters—including that of Csf1r—are composed exclusively of ‘distal’ elements that provide cell type-specific gene regulation by specialized TFs. Similar to CG-rich promoters, these also contain methylatable CG sites that are demethylated in a significant portion and show high polymerase activity. We conclude that this unusual class of promoters regulates cell type-specific gene expression in macrophages, and such a mechanism might exist in other cell types too.

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Section: Resultssupporting

confidence: 72%

Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression

Nagy,

Bojcsuk,

Tzerpos

et al. 2024

Nucleic Acids Research

Self Cite

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Targeting DNA Damage Response in Prostate and Breast Cancer

Wengner

Scholz

Haendler

2020

IJMS

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Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia–telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation.

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Alternatively Constructed Estrogen Receptor Alpha-Driven Super-Enhancers Result in Similar Gene Expression in Breast and Endometrial Cell Lines

Cited by 2 publications

References 65 publications

Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression

Lineage-determining transcription factor-driven promoters regulate cell type-specific macrophage gene expression

Targeting DNA Damage Response in Prostate and Breast Cancer

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