Biology subjects

Tzerpos, P.

Publications and source records attributed to Tzerpos, P..

4 recordsLinked to original sources

bioRxiv2025

Genome organizer SATB1 restrains the BACH1-cMAF axis that drives autoimmunity

The establishment of central tolerance in the thymus is governed by precise gene regulatory networks, but how disrupted chromatin architecture leads to autoimmunity is unclear. The genome organizer SATB1 is essential for T cell development and its loss triggers a severe autoimmune phenotype. Here, we identify a pathogenic transcriptional axis, involving BACH1 and cMAF, that is unleashed upon SATB1 deletion. Using integrated multi-omics in T cell-specific Satb1-knockout mice, we demonstrate that SATB1 constrains BACH1 chromatin occupancy. In its absence, BACH1 redistributes to promoter-proximal regions and SATB1-bound immune loci, where it facilitates the recruitment of the transcription factor cMAF. This BACH1-cMAF complex drives a pro-inflammatory transcriptional program in thymocytes, which seeds the periphery and results in a systemic autoimmune disease. Strikingly, genetic ablation of Bach1 in Satb1-deficient mice rescues the pathology, normalizes immunity and prevents mortality. Furthermore, genetic or pharmacological inhibition of cMAF ameliorates the disease. The pro-inflammatory signature in mutant T cells overlaps with T cells from Systemic Lupus Erythematosus (SLE) patients. Our findings reveal a BACH1-cMAF axis that is derepressed upon SATB1 loss and bridges disrupted thymic chromatin organization to peripheral autoimmunity, nominating new therapeutic targets.

molecular biology↗

bioRxiv2024

Epigenomic programming of peripheral monocytes determines their transcriptional response to the tumor microenvironment

Classical monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in determining transcriptional responses to the tissue environment. It is unknown to what extent the epigenetic landscape of peripheral monocytes is rewired by cancer and how this could shape their transcriptional response upon recruitment to the tumor microenvironment. Here we used a combination of genome-wide assays for mRNA expression, chromatin accessibility and multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) in a mouse model to investigate changes in the epigenomic landscape of peripheral monocytes. We then linked these epigenetic alterations to gene expression changes in monocytes occurring in the periphery or during tumor infiltration. We found that the distal tumor caused extensive remodeling of both H3K4me3+ promoters and H3K4me1+ enhancers in peripheral monocytes. Specifically, this involved the repression of interferon-responsive promoters and enhancers as well as the establishment of enhancers harboring binding motifs for transcription factors downstream of inflammatory and cytokine signaling pathways. The enhancers altered in the periphery could be linked to sustained gene expression changes which were less likely to be reversed in the tumor microenvironment. In addition, genes activated upon tumor infiltration showed prior epigenetic priming in peripheral monocytes. Overall, these results indicate that the epigenomic landscape of peripheral monocytes is altered in response to a distal tumor, and this could shape the transcriptional response of monocytes when they encounter microenvironmental signals upon infiltrating the tumor.

immunology↗

bioRxiv2021

SATB1 undergoes isoform-specific phase transitions in T cells

Intra-thymic T cell development is coordinated by the regulatory actions of SATB1 genome organizer. In this report, we show that SATB1 is involved in the regulation of transcription and splicing, both of which displayed deregulation in Satb1 knockout murine thymocytes. More importantly, we characterized a novel SATB1 protein isoform and described its distinct biophysical behavior, implicating potential functional differences compared to the commonly studied isoform. SATB1 utilized its prion-like domains to transition through liquid-like states to aggregated structures. This behavior was dependent on protein concentration as well as phosphorylation and interaction with nuclear RNA. Notably, the long SATB1 isoform was more prone to aggregate following phase separation. Thus, the tight regulation of SATB1 isoforms expression levels alongside with protein post-translational modifications, are imperative for SATB1s mode of action in T cell development. Our data indicate that deregulation of these processes may also be linked to disorders such as cancer.

molecular biology↗

bioRxiv2021

The 3D enhancer network of the developing T cell genome is controlled by SATB1

Mechanisms of tissue-specific gene expression regulation via spatial coordination of gene promoters and distal regulatory elements are still poorly understood. We investigated the 3D genome organization of developing murine T cells and identified SATB1, a tissue-specific genome organizer, enriched at the anchors of promoter-enhancer chromatin loops. We assessed the function of SATB1 in T cell chromatin organization and compared it to the conventional genome organizer CTCF. SATB1 builds a more refined layer of genome organization upon a CTCF scaffold. To understand the regulatory implications of SATB1 loopscape structure, we generated Satb1fl/flCd4-Cre+ (Satb1 cKO) conditional knockout animals which suffered from autoimmunity. We aimed to identify molecular mechanisms responsible for the deregulation of the immune system in Satb1 cKO animals. H3K27ac HiChIP and Hi-C experiments indicated that SATB1 primarily mediates promoter-enhancer loops affecting master regulator genes (such as Bcl6), the T cell receptor locus and adhesion molecule genes, collectively being critical for cell lineage specification and immune system homeostasis. Our findings unravel the function of a tissue-specific factor that controls transcription programs, via spatial chromatin arrangements complementary to the chromatin structure imposed by ubiquitously expressed genome organizers.

molecular biology↗