OVERCOMING THE CHROMATIN BARRIER: A HEMATOPOIETIC PIONEER TRANSCRIPTION FACTOR PAVES THE WAY FOR SITE-SPECIFIC ATP-DEPENDENT NUCLEOSOME REMODELING

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Immunology
Discipline
Biology
Biochemistry, Biophysics, and Structural Biology
Immunology and Infectious Disease
Subject
chromatin
hematopoiesis
linker histone
transcription factor
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Copyright date
2022
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Author
Frederick, Megan, Anna
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Abstract

Pioneer transcription factors engage nucleosomal DNA in chromatin to initiate gene regulatory events that control cell fate. To determine how different pioneer transcription factors initiate the formation of a locally accessible environment within silent, compacted chromatin and collaborate with an ATP-dependent chromatin remodeler, we generated nucleosome arrays in vitro with a central nucleosome that can be targeted by the hematopoietic ETS factor PU.1 and bZIP factors C/EBPα, and C/EBPβ. Each class of factor can expose target nucleosomes on linker histone-compacted arrays, but with different hypersensitivity patterns, as discerned by long-read sequencing. The DNA binding domain of PU.1 is sufficient for mononucleosome binding but requires an additional intrinsically disordered domain to bind and open compacted chromatin. The canonical mammalian SWI/SNF (BAF) complex, cBAF, was unable to act upon two forms of locally open chromatin, in the presence of linker histone, unless cBAF was enabled by the acidic- and glutamine-enriched transactivation domain of PU.1. However, cBAF complexes potentiate the nucleosome binding DBD of PU.1 to weakly open chromatin in the absence of the PU.1 unstructured domain. Together our findings provide a mechanism for how pioneer factors initially target chromatin structures to provide specificity for action by nucleosome remodelers that further open local domains.

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Zaret, Kenneth, S
Date of degree
2022
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