Biology subjects

Kalocsay, M.

Publications and source records attributed to Kalocsay, M..

23 records · Page 2Linked to original sources

bioRxiv2020

Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis

Recent studies demonstrated that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in kidneys of patients with chronic kidney disease, fibrotic lungs of patients with idiopathic pulmonary fibrosis, fibrotic human kidney organoids, and fibrotic mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts was sufficient to enhance glycolysis and increase alpha smooth muscle actin (SMA) and collagen1 levels. Knockout of COUP-TFII decreased glycolysis and collagen1 levels in fibroblasts. Chip-qPCR assays revealed the binding of COUP-TFII on the promoter of PGC1, a critical regulator of mitochondrial genesis and oxidative metabolism. Overexpression of COUP-TFII reduced the cellular level of PGC1. In conclusion, COUP-TFII mediates fibrosis by serving as a key regulator of the shift in cellular metabolism of interstitial pericytes/fibroblasts from oxidative respiration to aerobic glycolysis. The fibrogenic response may share a common pathway in different organ injury and failure. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potential other organ fibrosis.

cell biology↗

bioRxiv2019

An RNA degradation complex required for silencing of Polycomb target genes

Polycomb Repressive Complex (PRC) 1 and 2 are histone-modifying and chromatin-binding complexes that are required for silencing of developmental regulatory genes and genes that control cellular proliferation. Their gene silencing functions are thought to involve chromatin compaction and condensate formation but whether other mechanisms contribute to silencing is unknown. Here we show that the rixosome, a conserved RNA degradation complex with roles in ribosomal RNA processing and heterochromatic RNA degradation in fission yeast, associates with human PRC complexes, is recruited to promoters of Polycomb target genes in differentiated cell lines and embryonic stem cells, and is required for efficient silencing of Polycomb target genes. These findings reveal an unanticipated role for RNA degradation in Polycomb-mediated silencing.

molecular biology↗

bioRxiv2019

An RNA Degradation Complex Required for Spreading and Epigenetic Inheritance of Heterochromatin

Heterochromatin assembly requires the methylation of histone H3 lysine 9 by the Clr4(Suv39h) methyltransferase and both the spreading and epigenetic inheritance of heterochromatin involve the recognition of H3K9me-containing nucleosomes by Clr4 and catalysis of H3K9me on adjacent nucleosomes. How this read-write mechanism overcomes obstacles posed by RNA polymerase II and nascent RNA in its path is not fully understood. Here we identify a role for the highly conserved and essential Rix1-containing complex (here referred to as the rixosome), with known RNA endonuclease and polynucleotide kinase activities required for ribosomal RNA (rRNA) processing, in spreading and epigenetic inheritance of heterochromatin. Viable mutations in rixosome subunits that disrupt its association with Swi6/HP1 fail to localize to heterochromatin, lead to accumulation of heterochromatic RNAs, and block spreading of H3K9me and silencing away from nucleation sites into actively transcribed regions. These findings reveal a new pathway for degradation of heterochromatic RNAs with essential roles in heterochromatin spreading and inheritance.

molecular biology↗

bioRxiv2019

The protein repertoire in early vertebrate embryogenesis

We present an unprecedentedly comprehensive characterization of protein dynamics across early development in Xenopus laevis, available immediately via a convenient Web portal. This resource allows interrogation of the protein expression data in conjunction with other data modalities such as genome wide mRNA expression. This study provides detailed data for absolute levels of [~]14K unique Xenopus proteins representing homologues of [~]9K unique human genes - a rich resource for developmental biologists. The purpose of this manuscript is limited to presenting and releasing the data browser.\n\nHighlightsO_LIRelative protein expression from stage IV oocyte, blastula, gastrula, neurula, and early organogenesis\nC_LIO_LIBiological triplicates with confidence intervals on protein expression reflect certainty in dynamic patterns\nC_LIO_LIConvenient time-series Web-browser integrated with the multi-media Xenbase portal\nC_LIO_LIGene-symbol search and multi-gene protein/mRNA juxtaposition capabilities\nC_LI

developmental biology↗

bioRxiv2018

YAP independently regulates cell size and population growth dynamics via non-cell autonomous mediators

The Hippo pathway, in which changes at the cell surface and in the extracellular environment control the activity of a downstream transcription factor, known as YAP in mammalian cells and Yorkie in Drosophila, has recently taken center-stage as perhaps the most important pathway in metazoans for controlling organ size. In intact tissues YAP activity is inhibited and the organ does not overgrow. When the organ is damaged, YAP is active and necessary for growth and regeneration to occur. The exact process by which YAP drives organ and tissue growth is not fully understood, although it is known to affect both cell size and cell number. Since cell size and proliferation are highly interdependent in many cultured cell studies, we investigated the role of YAP in the simultaneous regulation of both cell size and number. Our experiments reveal that YAP controls both cell size and cell proliferation by independent circuits, and that it affects each process non-cell autonomously via extracellular mediators. We identify that CYR61, a known secreted YAP target, is the major regulator of the non-cell autonomous increase in cell number, but does not affect cell size. The molecular identity of the non-cell autonomously acting mediator of cell size is yet to be identified.

cell biology↗