The pioneer factor activity of c-Myb involves recruitment of p300 and induction of histone acetylation followed by acetylation-induced chromatin dissociation

Abstract

BackgroundThe concept of pioneer transcription factors is emerging as an essential part of the epigenetic regulation, taking place during cell development and differentiation. However, the precise molecular mechanism underlying pioneer factor activity remains poorly understood. We recently reported that the transcription factor c-Myb acts as a pioneer factor in haematopoiesis, and a point mutation in its DNA binding domain, D152V, is able to abrogate this function.ResultsHere, we show that specific histone modifications, including H3K27ac, prevent binding of c-Myb to histone tails, representing a novel effect of histone modifications, namely restricting binding of a pioneer factor to chromatin. Furthermore, we have taken advantage of the pioneer-defect D152V mutant to investigate mechanisms of c-Myb’s pioneer factor activity. We show that c-Myb-dependent transcriptional activation of a gene in inaccessible chromatin relies on c-Myb binding to histones, as well as on c-Myb interacting with the histone acetyltransferase p300. ChIP assays show that both wild type and the D152V mutant of c-Myb bind to a selected target gene at its promoter and enhancer, but only wild-type c-Myb causes opening and activation of the locus. Enhancement of histone acetylation restores activation of the same gene in the absence of c-Myb, suggesting that facilitating histone acetylation is a crucial part of the pioneer factor function of c-Myb.ConclusionsWe suggest a pioneer factor model in which c-Myb binds to regions of closed chromatin and then recruits histone acetyltransferases. By binding to histones, c-Myb facilitates histone acetylation, acting as a cofactor for p300 at c-Myb bound sites. The resulting H3K27ac leads to chromatin opening and detachment of c-Myb from the acetylated chromatin. We propose that the latter phenomenon, acetylation-induced chromatin dissociation, represents a mechanism for controlling the dynamics of pioneer factor binding to chromatin.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0208-y) contains supplementary material, which is available to authorized users.

The essential glucose transporter GLUT1 is epigenetically upregulated by C/EBPβ and WT1 during decidualization of the endometrium

“…5 A ). p300 is a transcription coactivator that has histone acetyltransferase (HAT) activities and induces H3K27ac ( 26 , 27 , 28 ). p300 interacts with both C/EBPβ and WT1 ( 29 , 30 , 31 ).…”

“…In general, chromatin remodeling regulated by histone modifications is induced by the recruitment of pioneer transcription factors, which is responsible for the initiation of the epigenetic changes ( 32 , 33 , 41 ). These factors recruit cofactors that have histone acetyltransferase (HAT) activities, such as p300, to induce H3K27ac ( 27 , 28 ). C/EBPβ has been suggested to act as a pioneer factor in a variety of cells ( 41 , 42 , 43 , 44 , 45 ).…”

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

“…Both the diverse functionality of target genes and our in vitro experiments suggest a possible broad functional impact of SOX11 on the NB phenotype. Here, we further focussed on the possible role of SOX11 as epigenetic master regulator, given its direct role in regulation of components of the PRC2 and SWI/SNF complexes, the DNMT1 recruiting protein UHRF1 and pioneering TF c-MYB 22 . While these targets require further individual functional validation, the finding of multiple functional targets implicated in a broad range of essential epigenetic regulatory processes is intriguing.…”

Identification of a master regulator of differentiation inToxoplasma

“…Myb domain-containing proteins are widespread among eukaryotes, and have been implicated in the regulation of encystation in Entamoeba and Giardia, along with a wide variety of stress responses in plants (Ambawat et al, 2013;Dubos et al, 2010;Ehrenkaufer et al, 2009;Huang et al, 2008;Sun et al, 2002). In humans, c-Myb is thought to function as a pioneer transcription factor, binding to chromatin and recruiting histone acetyltransferases to commit cells to specific hematopoietic lineages (Fuglerud et al, 2018;Sandberg et al, 2005). Among apicomplexan parasites, a Myb domain-containing protein has been identified as important for erythrocytic growth of Plasmodium falciparum, suggesting that other family members likely play important roles throughout the phylum (Boschet et al, 2004;Gissot et al, 2005).…”