Efthymiadou, A. | Search bioRxiv

bioRxiv2025

Non-redundant roles of the HDAC3 corepressor complex subunits SMRT and NCOR in controlling inflammatory and metabolic macrophage pathways

Transcription factors and coregulators coordinate inflammatory and metabolic pathways in macrophages through epigenetic and transcriptional mechanisms. The HDAC3 corepressor complex plays fundamental roles in these mechanisms, with the homologous subunits SMRT and NCOR being critical for complex assembly and interactions with transcription factors and chromatin. However, the relative contribution of SMRT and NCOR in controlling complex-dependent macrophage pathways remains poorly understood. Here, we assessed their genome-wide roles in mouse macrophage RAW264.7 cells and in bone marrow-derived macrophages. Transcriptome analysis upon corepressor depletion identified six differentially expressed gene clusters. SMRT depletion primarily upregulated inflammation-related pathways, NCOR depletion primarily upregulated metabolism-related pathways. Epigenome analysis revealed that corepressor depletion differentially altered chromatin accessibility and H3K27 acetylation, consistent with transcriptome changes. Cistrome analysis revealed that both corepressors differentially influence each other at chromatin. SMRT uniquely controls the chromatin binding and nuclear localization of NCOR, GPS2 and HDAC3, thus acting as the chromatin anchor for the corepressor complex. Finally, corepressor depletion differentially modulated macrophage reprogramming in response to TLR4, IL4 and LXR signaling. Overall, our study reveals a hitherto underappreciated non-redundant role of SMRT and NCOR in coordinating chromatin accessibility, H3K27 acetylation, enhancer activity and transcription to differentially regulate inflammatory and metabolic macrophage pathways. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/653058v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d9f2dforg.highwire.dtl.DTLVardef@1d81386org.highwire.dtl.DTLVardef@e9e536org.highwire.dtl.DTLVardef@1c74c15_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2019

Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

Mutations in the thyroid hormone receptor 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor 1 is required for normal neural progenitor cell proliferation and organisation in human cerebral cortical development. They also exemplify novel quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

developmental biology↗