Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA641206 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12072422.fastq.gz | Fastqsanger.gz | |||
| SRR12072423.fastq.gz | Fastqsanger.gz | |||
| SRR12072424.fastq.gz | Fastqsanger.gz | |||
| SRR12072425.fastq.gz | Fastqsanger.gz | |||
| SRR12072426.fastq.gz | Fastqsanger.gz |
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Project description:The physiological adaptation to cold environmental temperatures involves the remodeling of energy-storing white adipose tissue (WAT) into an energy-burning thermogenic phenotype, characterized by the emergence of multi-locular beige adipocytes. To date, the full array of cold-responsive cells within WAT that mediate thermogenic remodeling remain undefined. Here, we demonstrate that distinct perivascular PDGFRb+ adipocyte precursor cell (APC) subpopulations are differentially sensitive to cold temperatures in vivo. One day of cold exposure elicits striking transcriptional changes in DPP4+ PDGFRb+ APCs, whereas committed DPP4- PDGFRb+ preadipocytes appear comparatively much less responsive. This adaptation includes beta-adrenergic receptor mediated induction in the expression of the pro-thermogenic cytokine, IL-33. DPP4+ PDGFRb+ cells represent the sole source of IL-33 within inguinal WAT of adult mice. Doxycycline-inducible deletion of Il33 in PDGFRb+ cells at the onset of cold exposure significantly compromises the thermogenic remodeling of WAT without directly impacting the differentiation capacity of APCs per se. Together, these studies reveal the presence of a cold-responsive progenitor cell subpopulation in adult WAT and highlight their ability to regulate tissue plasticity through the production of immunological factors.
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Project description:PU.1 is a prototype master transcription factor (TF) of hematopoietic cell differentiation with diverse roles in different lineages. Analysis of its genome-wide binding pattern across PU.1 expressing cell types revealed manifold cell type-specific binding patterns. They are not consistent with the epigenetic and chromatin constraints to PU.1 binding observed in vitro, suggesting that PU.1 requires auxiliary factors to access DNA in vivo. Using a model of transient mRNA expression we show that PU.1 induction leads to the extensive remodeling of chromatin, redistribution of partner transcription factors and rapid initiation of a myeloid gene expression program in heterologous cell types. By probing PU.1 mutants for defects in chromatin access and screening for PU.1 proximal proteins in vivo, we found that its N-terminal acidic domain was required for the recruitment of SWI/SNF remodeling complexes, de novo chromatin access and stable binding as well as the redistribution of partner TFs.
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