Temporal autoregulation during human PU.1 locus SubTAD formation
| Autor: | Stefan Gröschel, Klaus Wethmar, Claudia Gebhard, Daniel Schuetzmann, Michael Rehli, Andre Weilemann, Thorsten König, Eric M.J. Bindels, Carolin Walter, Julia Minderjahn, Frank Rosenbauer, Boet van Riel, Ruud Delwel, Chiara Perrod, Alexander Tönges, Tabea Erdmann, Sabrina Kruse, Martin Dugas, Georg Lenz |
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| Přispěvatelé: | Hematology |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Transcriptionally active chromatin Regulation of gene expression Immunology Myeloid leukemia Locus (genetics) Cell Biology Hematology Biology Biochemistry Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Autoregulation Epigenetics Gene Transcription factor |
| Zdroj: | Blood, 132(25), 2643-2655. American Society of Hematology |
| ISSN: | 0006-4971 |
| Popis: | Epigenetic control of gene expression occurs within discrete spatial chromosomal units called topologically associating domains (TADs), but the exact spatial requirements of most genes are unknown; this is of particular interest for genes involved in cancer. We therefore applied high-resolution chromosomal conformation capture sequencing to map the three-dimensional (3D) organization of the human locus encoding the key myeloid transcription factor PU.1 in healthy monocytes and acute myeloid leukemia (AML) cells. We identified a dynamic ∼75-kb unit (SubTAD) as the genomic region in which spatial interactions between PU.1 gene regulatory elements occur during myeloid differentiation and are interrupted in AML. Within this SubTAD, proper initiation of the spatial chromosomal interactions requires PU.1 autoregulation and recruitment of the chromatin-adaptor protein LDB1 (LIM domain–binding protein 1). However, once these spatial interactions have occurred, LDB1 stabilizes them independently of PU.1 autoregulation. Thus, our data support that PU.1 autoregulates its expression in a “hit-and-run” manner by initiating stable chromosomal loops that result in a transcriptionally active chromatin architecture. |
| Databáze: | OpenAIRE |
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