Information encoded in the DNA is interpreted in context of chromatin – a complex of nucleic acids and proteins, of which histones are the major component. Histones are locally modified by a vast number of factors, thus mediating the interface between the genome and regulatory inputs. This role of chromatin is exemplified by an observation that sequence-specific DNA-binding transcription factors occupy unique sites and regulate non-overlapping genes in distinct cell types, despite identical set of chromosomes in every cell. Collective action of several master-regulator transcription factors in hematopoietic stem/progenitor cells gives rise to differentiated blood cells. Aberrant transcriptio...
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Information encoded in the DNA is interpreted in context of chromatin – a complex of nucleic acids and proteins, of which histones are the major component. Histones are locally modified by a vast number of factors, thus mediating the interface between the genome and regulatory inputs. This role of chromatin is exemplified by an observation that sequence-specific DNA-binding transcription factors occupy unique sites and regulate non-overlapping genes in distinct cell types, despite identical set of chromosomes in every cell. Collective action of several master-regulator transcription factors in hematopoietic stem/progenitor cells gives rise to differentiated blood cells. Aberrant transcriptional regulation is a hallmark of leukemogenesis, and mutations in chromatin factors are the most prevalent drivers of acute myeloid leukemia (AML), with driver mutations in only ten chromatin factors accounting for over 50% of all AML cases. Yet how chromatin landscape affects transcription factor function remains largely unknown. We hypothesize that transcription factor association and activity are modulated by histone post-translational modifications (PTMs) proximal to the transcription factor binding site. In this model, transcription factors integrate local chromatin context to achieve cell-specific gene regulation. We predict that aberrant transcription factors and histone PTMs cooperate in malignancy, to induce and sustain oncogenic transformation. Focusing on paradigmatic transcription factors RUNX1 and CBFB and AML model, we will (a) in an unbiased manner, identify the PTMs of histones immediately neighboring the occupied transcription factor binding sites, and (b) disrupt specific “writers” of these modifications to investigate their role in transcription factor occupancy and resulting effects in AML. These studies will pioneer new understanding of cooperativity between chromatin and transcription factors, and identify new rational therapeutic approaches to leukemia.
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