Publications by authors named "Natalia Kunowska"

Hematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin-dependent kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. Herein, we describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal, and differentiation in activated HSCs.

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During ribosome biogenesis a plethora of assembly factors and essential enzymes drive the unidirectional maturation of nascent pre-ribosomal subunits. The DEAD-box RNA helicase Dbp10 is suggested to restructure pre-ribosomal rRNA of the evolving peptidyl-transferase center (PTC) on nucleolar ribosomal 60S assembly intermediates. Here, we show that point mutations within conserved catalytic helicase-core motifs of Dbp10 yield a dominant-lethal growth phenotype.

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Article Synopsis
  • * The study mapped quantitative trait loci (QTL) linked to gene expression and chromatin activity in Treg cells, identifying 133 colocalizing loci that associate with immune disease variants.
  • * It highlighted seven known drug targets for repurposing and suggested 63 potential targets for drug development, marking a significant step in understanding how immune disease variants impact Treg cell function.
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Protein kinases play an important role in cellular signaling pathways and their dysregulation leads to multiple diseases, making kinases prime drug targets. While more than 500 human protein kinases are known to collectively mediate phosphorylation of over 290,000 S/T/Y sites, the activities have been characterized only for a minor, intensively studied subset. To systematically address this discrepancy, we developed a human kinase array in Saccharomyces cerevisiae as a simple readout tool to systematically assess kinase activities.

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Disturbances in lipid homeostasis can cause mitochondrial dysfunction and lipotoxicity. Perilipin 5 (PLIN5) decorates intracellular lipid droplets (LDs) in oxidative tissues and controls triacylglycerol (TG) turnover via its interactions with adipose triglyceride lipase and the adipose triglyceride lipase coactivator, comparative gene identification-58. Furthermore, PLIN5 anchors mitochondria to the LD membrane via the outermost part of the carboxyl terminus.

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  • * Conditional knockout of RUNX1 in mouse B cells causes them to enter S-phase more quickly after BCR activation, indicating its role in controlling gene expression related to cell cycle dynamics.
  • * RUNX1 interacts with chromatin remodeling proteins to regulate several genes related to B cell activation, which suggests it may play a role in B cell tolerance and immune response regulation.
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It is often unclear how genetic variation translates into cellular phenotypes, including how much of the coding variation can be recovered in the proteome. Proteogenomic analyses of heterogenous cell lines revealed that the genetic differences impact mostly the abundance and stoichiometry of protein complexes, with the effects propagating post-transcriptionally via protein interactions onto other subunits. Conversely, large scale binary interaction analyses of missense variants revealed that loss of interaction is widespread and caused by about 50% disease-associated mutations, while deep scanning mutagenesis of binary interactions identified thousands of interaction-deficient variants per interaction.

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Many of the key cellular processes including establishing the cell's identity are governed by chromatin proteins. Mapping their binding on the level of a single cell would give us important insights into a new dimension of cellular heterogeneity. However, ChIP-seq, the main method to study protein-DNA interaction in the chromatin context, has proven very challenging to scale down.

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DNA methylation at cytosine is a major epigenetic mark, heavily implicated in controlling key cellular processes such as development and differentiation, cellular memory, or carcinogenesis. Bisulfite treatment in conjunction with next generation sequencing has been a powerful tool for studying this modification in a quantitative manner in the context of the whole genome and with a single nucleotide resolution. This chapter describes a protocol for bisulfite sequencing adapted to a single-cell format that allows for capturing the methylation signal from up to 50% CpG nucleotides in each cell.

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Article Synopsis
  • The innate immune response serves as the body's first line of defense against pathogens and varies among different types of cells, requiring a balance between a strong reaction and self-protection.
  • Researchers studied the genetic differences in immune responses across species and found notable variations in gene expression, particularly in cytokines and chemokines, which play key roles in immune signaling.
  • Conversely, genes regulating these immune responses, like transcription factors and kinases, are more conserved and exhibit low variability, suggesting that evolution has optimized these regulatory mechanisms to ensure an effective but controlled immune response.
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The large number of chemical modifications that are found on the histone proteins of eukaryotic cells form multiple complex combinations, which can act as recognition signals for reader proteins. We have used peptide capture in conjunction with super-SILAC quantification to carry out an unbiased high-throughput analysis of the composition of protein complexes that bind to histone H3K9/S10 and H3K27/S28 methyl-phospho modifications. The accurate quantification allowed us to perform Weighted correlation network analysis (WGCNA) to obtain a systems-level view of the histone H3 histone tail interactome.

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Methylated histones H3K9 and H3K27 are canonical epigenetic silencing modifications in metazoan organisms, but the relationship between the two modifications has not been well characterized. H3K9me3 coexists with H3K27me3 in pluripotent and differentiated cells. However, we find that the functioning of H3K9me3 is altered by H3S10 phosphorylation in differentiated postmitotic osteoblasts and cycling B cells.

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The Polycomb Group (PcG) of chromatin modifiers regulates pluripotency and differentiation. Mammalian genomes encode multiple homologs of the Polycomb repressive complex 1 (PRC1) components, including five orthologs of the Drosophila Polycomb protein (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8). We have identified Cbx7 as the primary Polycomb ortholog of PRC1 complexes in embryonic stem cells (ESCs).

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Demethylation at distinct lysine residues in histone H3 by lysine-specific demethylase 1 (LSD1) causes either gene repression or activation. As a component of co-repressor complexes, LSD1 contributes to target gene repression by removing mono- and dimethyl marks from lysine 4 of histone H3 (H3K4). In contrast, during androgen receptor (AR)-activated gene expression, LSD1 removes mono- and dimethyl marks from lysine 9 of histone H3 (H3K9).

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Posttranslational modifications of histones such as methylation, acetylation and phosphorylation regulate chromatin structure and gene expression. Here we show that protein-kinase-C-related kinase 1 (PRK1) phosphorylates histone H3 at threonine 11 (H3T11) upon ligand-dependent recruitment to androgen receptor target genes. PRK1 is pivotal to androgen receptor function because PRK1 knockdown or inhibition impedes androgen receptor-dependent transcription.

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Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel transcriptional corepressor with inhibitor of histone acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood.

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