Biology subjects

Borchers, A.

Publications and source records attributed to Borchers, A..

6 recordsLinked to original sources

bioRxiv2025

ZNF512B associates with mitotic spindles, regulates metaphase exit and is crucial for stem cell differentiation

Zinc finger proteins are a large family of DNA-binding factors that play key roles in diverse cellular processes including gene regulation, RNA metabolism and cell cycle control. The zinc finger protein ZNF512B has recently been implicated in chromatin organization and transcriptional repression through its direct interaction with the nucleosome remodeling and deacetylase (NuRD) complex, its DNA-binding ability, and its association with the histone variant H2A.Z. Here, we uncover a previously unrecognized role for ZNF512B that is independent of both its zinc finger domains and NuRD association. We identify ZNF512B as a spindle-associated factor that regulates progression through mitosis, specifically controlling metaphase exit. ZNF512Bs N-terminal internal region, which contains 25 repeats of a six-residue motif predicted to form a {beta}-helix structure, is required and sufficient for its spindle interaction. Elevated ZNF512B levels result in a profound metaphase arrest that is ultimately lethal, a phenotype arising from the combined activity of its spindle-binding and chromatin-tethering functions. Conversely, ZNF512B depletion accelerates stem cell proliferation, impairs differentiation, and upregulates genes linked to cell cycle progression. Our findings position ZNF512B as a multifunctional protein that acts as a transcriptional repressor, a chromatin aggregator and a novel metaphase exit regulator through spindle fiber binding.

molecular biology↗

bioRxiv2024

Spatio-temporal interaction of immune and renal cells determines glomerular crescent formation in autoimmune kidney disease

Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney disease with the worst prognosis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, anti-glomerular basement membrane (anti-GBM) and lupus nephritis are the most common causes of RPGN and are characterized by the formation of glomerular crescents and infiltration of leukocytes that eventually lead to glomerulosclerosis and kidney failure. In this work, we used high-resolution spatial transcriptomics of 32 ANCA, 19 lupus nephritis, 6 anti-GBM, and 6 control patients to understand how intercellular signaling between immune and renal tissue cells leads to renal inflammation and glomerular injury. Using 3,218,210 immune and kidney cells, we observed that the biological pathways involved in the sequence of glomerular crescent formation are similar across the diseases. While innate immune cells infiltrated the glomerular compartment relatively early, later increases in adaptive immune cells were largely restricted to the periglomerular regions. These changes in immune cells temporally correlated with increases in glomerular parietal epithelial (PEC) and fibrotic mesangial cells, suggesting disease-relevant functional signaling between these immune and renal cells. Cell communication analysis revealed early disease PDGF signaling from epithelial and mesangial cells to PECs, causing their activation and proliferation. At later stages, TGF-{beta} signaling from macrophages, T cells, epithelial cells, and mesangial cells to PECs triggered the expression of extracellular matrix components resulting in glomerulosclerosis. Our results highlight a spatio-temporally conserved progression into glomerular crescents and sclerosis for ANCA, lupus nephritis, and anti-GBM disease, which is driven by consecutive PDGF and TGF-{beta} signaling to PECs.

immunology↗

bioRxiv2023

Emergence and suppressive function of Tr1 cells in glomerulonephritis

T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, high expression of IL-10, CD49b, and LAG3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis, the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and moreover, whether they exhibit regulatory function during glomerulonephritis has not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic glomerulonephritis and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10-producing CD4+ T cells infiltrate the kidneys during glomerulonephritis progression. Using single-cell RNA- sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic glomerulonephritis in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, e.g. as T- cell therapy. Thus, our study provides proof of concept for Tr1 cell-based therapies in experimental glomerulonephritis.

immunology↗

bioRxiv2022

GM-CSF drives immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12

Glomerulonephritis is a group of immune-mediated diseases that cause inflammation within the glomerulus and adjacent compartments of the kidney and is a major cause of end-stage renal disease. T cells are among the main drivers of glomerulonephritis. However, the T cell subsets, cytokine networks, and downstream effector mechanisms that lead to renal tissue injury are largely unknown, which has hindered the development of targeted therapies. Here we identify a population of GM-CSF-producing T cells that accumulates in the kidneys of patients with ANCA-associated glomerulonephritis, infiltrates the renal tissue in a mouse model of glomerulonephritis, and promotes tissue destruction and loss of renal function. Mechanistically, we show that GM-CSF producing T cells licence monocyte-derived cells to produce matrix metalloproteinase 12 (MMP12), which cleaves components of the glomerular basement membrane and exacerbates renal pathology. These findings provide a mechanistic rationale for the immunopathology of T cell-mediated diseases and identify the "GM-CSF - monocyte-derived cells - MMP12" pathway as a promising therapeutic target in treatment of glomerulonephritis.

immunology↗

bioRxiv2022

The H2A.Z.1/PWWP2A/NuRD-associated protein HMG20A controls early head and heart developmental transcription programs

Abstract/SummarySpecialized chromatin-binding proteins are required for DNA-based processes during development. We recently established PWWP2A as direct histone variant H2A.Z interactor involved in mitosis and cranial-facial development. Here, we identify the H2A.Z/PWWP2A-associated protein HMG20A as part of several chromatin-modifying complexes including NuRD, and show that it localizes to genomic regulatory regions. Hmg20a depletion causes severe head and heart developmental defects in Xenopus laevis. Our data indicate that craniofacial malformations are caused by defects in neural crest cell (NCC) migration and cartilage formation. These developmental defects are pheno-copied in HMG20A-depleted mESCs, which show inefficient differentiation into NCCs and cardiomyocytes (CMs). Accordingly, loss of HMG20A caused striking deregulation of transcription programs involved in epithelial- mesenchymal transition (EMT) and cardiac differentiation, thereby providing insights into the regulatory circuits controlled by HMG20A. Collectively, our findings implicate HMG20A as part of the H2A.Z/PWWP2A/NuRD-axis and reveal it as a key modulator of the intricate developmental transcription programs that guide NCC and cardiomyocyte differentiation.

molecular biology↗

bioRxiv2020

A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

Accumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector {gamma}{delta} T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing {gamma}{delta} T ({gamma}{delta}T17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired {gamma}{delta} TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector {gamma}{delta} T cell clusters. While immature {gamma}{delta} T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to {gamma}{delta}TCR usage. In adult samples, mature V{delta}1+ T cells segregated into exhausted PD-1hi and active PD-1low clusters. Among V{gamma}9V{delta}2+ T cell subsets, we identified distinct PLZF-positive effector {gamma}{delta} T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector {gamma}{delta} T cells including CCR6+ {gamma}{delta}T17 cells develop in the early fetal thymus and persist into adulthood.

immunology↗