Biology subjects

Fazleabas, A. T.

Publications and source records attributed to Fazleabas, A. T..

3 recordsLinked to original sources

bioRxiv2022

ARID1A maintains transcriptionally repressive H3.3 associated with CHD4-ZMYND8 chromatin interactions

ARID1A is a signature subunit of the mammalian SWI/SNF (BAF) chromatin remodeling complex and is mutated at a high rate in malignancies and benign diseases originating from the uterine endometrium. Through genome-wide analysis of human endometriotic epithelial cells, we show that more than half of ARID1A binding sites are marked by the variant histone H3.3, including active regulatory elements. ARID1A loss leads to H3.3 depletion at ARID1A bound active regulatory elements and a concomitant redistribution of H3.3 towards genic elements. ARID1A interactions with the repressive chromatin remodeler CHD4 (NuRD) are associated with H3.3-containing chromatin regulation. ZMYND8, the CHD4-interacting acetyl-histone H4 reader, specifies ARID1A-CHD4-H3.3 target regulatory activity towards histone H4 lysine 16 acetylation (H4K16ac) to repress super-enhancers. ARID1A, H3.3, CHD4, and ZMYND8 co-repress the expression of genes governing extracellular matrix, motility, adhesion, and epithelial-to-mesenchymal transition. Moreover, these gene expression alterations are observed in human endometriomas. Altogether, these studies demonstrate that cooperation among a histone reader and different types of chromatin remodelers safeguards the endometrium through transcriptionally repressive H3.3.

genetics↗

bioRxiv2022

Endometriotic Organoids as an In Vitro Model of Endometriotic Lesion Development.

The development and progression of endometriotic lesions are poorly understood, but immune cell dysfunction and inflammation are closely associated with the pathophysiology of endometriosis. A lack of suitable 3D in vitro models permitting the study of interactions between cell types and the microenvironment is a contributing factor. To address this limitation, we developed endometriotic organoids (EO) to explore the role of epithelial-stromal interactions and model peritoneal cell invasion associated with lesion development. Using a non-adherent microwell culture system, spherical organoids were generated with endometriotic epithelial cells (12Z) combined with immortalized endometriotic stromal cells (iEc-ESC) or immortalized uterine stromal cells (iHUF). Organoids self-organized with stromal cells occupying the center and epithelial cells on the periphery of the organoid. Endometriotic organoids (EO), containing iEc-ESC, resulted in the development of stratified 12Z epithelial cells compared to those with iHUF where the 12Z cells developed as a single layered epithelium. Transcriptomic analysis found 4,522 differentially expressed genes (DEG) between EO and 12Z/iHUF organoids, and the top DEG included increased expression of interleukins and prostaglandin synthase enzymes. An overlap of the EO DEG with baboon endometriotic lesions was highly significant. Finally, to mimic invasion of endometrial tissue into the peritoneum, a model was developed using EO and extracellular matrix containing human peritoneal mesothelial cells (LP9). Invasion of EO into the extracellular matrix-LP9 layer was increased in presence of estrogen or THP1-derived proinflammatory macrophages. Taken together, our results strongly support the concept that EO are an appropriate model for dissecting mechanisms that contribute to endometriotic lesion development. One Sentence SummaryEndometriotic organoids are an appropriate model to study epithelial-stromal interactions and model cell invasion associated with lesion development.

cell biology↗

bioRxiv2020

Endometrial epithelial ARID1A is critical for uterine gland function in early pregnancy establishment

Though endometriosis and infertility are clearly associated, the pathophysiological mechanism remains unclear. Previous work has linked endometrial ARID1A loss to endometriosis-related endometrial non-receptivity. Here, we show in mice that ARID1A binds and regulates transcription of the Foxa2 gene required for endometrial gland function. Uterine specific deletion of Arid1a compromises gland development and diminishes Foxa2 and Lif expression. Deletion of Arid1a with Ltf-iCre in the adult mouse endometrial epithelium preserves gland development while still compromising gland function. Mice lacking endometrial epithelial Arid1a are severely sub-fertile due to defects in implantation, decidualization, and endometrial receptivity from disruption of the LIF-STAT3-EGR1 pathway. FOXA2 is also reduced in the endometrium of women with endometriosis in correlation with diminished ARID1A, and both ARID1A and FOXA2 are reduced in non-human primates induced with endometriosis. Our findings describe a role for ARID1A in the endometrial epithelium supporting early pregnancy establishment through the maintenance of gland function.

physiology↗