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 SATB1's mode of action in T cell development. Our data indicate that deregulation of these processes may also be linked to disorders such as cancer.
- Klíčová slova
- SATB1, T cells, chromatin organization, phase separation, prion,
- Publikační typ
- časopisecké články MeSH
GATA-1 and PU.1 are two important hematopoietic transcription factors that mutually inhibit each other in progenitor cells to guide entrance into the erythroid or myeloid lineage, respectively. PU.1 controls its own expression during myelopoiesis by binding to the distal URE enhancer, whose deletion leads to acute myeloid leukemia (AML). We herein present evidence that GATA-1 binds to the PU.1 gene and inhibits its expression in human AML-erythroleukemias (EL). Furthermore, GATA-1 together with DNA methyl Transferase I (DNMT1) mediate repression of the PU.1 gene through the URE. Repression of the PU.1 gene involves both DNA methylation at the URE and its histone H3 lysine-K9 methylation and deacetylation as well as the H3K27 methylation at additional DNA elements and the promoter. The GATA-1-mediated inhibition of PU.1 gene transcription in human AML-EL mediated through the URE represents important mechanism that contributes to PU.1 downregulation and leukemogenesis that is sensitive to DNA demethylation therapy.
- MeSH
- akutní erytroblastická leukemie genetika patologie MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- buněčná diferenciace genetika MeSH
- DNA-(cytosin-5-)methyltransferasa genetika metabolismus MeSH
- DNA-(cytosin-5)-methyltransferasa 1 MeSH
- genetická transkripce MeSH
- histony genetika MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- promotorové oblasti (genetika) MeSH
- protoonkogenní proteiny biosyntéza genetika metabolismus MeSH
- regulace genové exprese u leukemie MeSH
- trans-aktivátory biosyntéza genetika metabolismus MeSH
- transkripční faktor GATA1 genetika metabolismus MeSH
- vazba proteinů MeSH
- zesilovače transkripce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA-(cytosin-5-)methyltransferasa MeSH
- DNA-(cytosin-5)-methyltransferasa 1 MeSH
- DNMT1 protein, human MeSH Prohlížeč
- GATA1 protein, human MeSH Prohlížeč
- histony MeSH
- proto-oncogene protein Spi-1 MeSH Prohlížeč
- protoonkogenní proteiny MeSH
- trans-aktivátory MeSH
- transkripční faktor GATA1 MeSH
