BPTF Maintains Chromatin Accessibility and the Self-Renewal Capacity of Mammary Gland Stem Cells

Abstract

SummaryChromatin remodeling is a key requirement for transcriptional control of cellular differentiation. However, the factors that alter chromatin architecture in mammary stem cells (MaSCs) are poorly understood. Here, we show that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for MaSC self-renewal and differentiation of mammary epithelial cells (MECs). BPTF depletion arrests cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. Moreover, genome-wide analysis of DNA accessibility following genetic or chemical inhibition, suggests a role for BPTF in maintaining the open chromatin landscape at enhancers regions in MECs. Collectively, our study implicates BPTF in maintaining the unique epigenetic state of MaSCs.

NUP98‐BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy

“…BPTF contains chromatin interacting modules, but no reported catalytic domains. The NURF complex is reported to regulate homeotic gene expression and cell fate decisions . BPTF is shown to target the HOXA9 locus via the combinatorial action of its C‐terminal PHD‐Bromodomain tandem, and to sustain c‐MYC transcriptional activity in tumors .…”

“…The NURF complex is reported to regulate homeotic gene expression 13,21,22 and cell fate decisions. [23][24][25] BPTF is shown to target the HOXA9 locus via the combinatorial action of its C-terminal PHD-Bromodomain tandem, 21 and to sustain c-MYC transcriptional activity in tumors. 26 Although the human BPTF transcript variants annotated thus far code for a single PHD domain, the fly BPTF protein homolog Nurf301 is reported to harbor two closely spaced C-terminal PDH domains followed by the bromodomain 13 (Supporting Information Figure S3).…”

Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

“…28 Lastly, BPTF maintains chromatin accessibility and the self-renewal capacity of mammary gland stem cells. 29 Here, we describe phenotypic manifestations of germline loss-of-function (LoF) variants in BPTF in ten unrelated individuals with an autosomal-dominant neurodevelopmental disorder and show with an in vivo zebrafish model that bptf is relevant to brain development and craniofacial patterning.…”

The Chromatin Remodeler BPTF Activates a Stemness Gene-Expression Program Essential for the Maintenance of Adult Hematopoietic Stem Cells

“…In related research, BPTF acts as a crucial regulator of mammary gland and epidermal stem cells ( Frey et al., 2017 , Mulder et al., 2012 ), melanocytes ( Koludrovic et al., 2015 ), and T cells ( Landry et al., 2011 , Wu et al., 2016 ). Here, an intriguing question is how the general chromatin regulator BPTF controls a defined yet distinct gene-expression program among different cell lineages.…”

“…While global knockout of Bptf in mice leads to lethality on embryonic day 8.5, demonstrating its requirement for early development ( Landry et al., 2008 ), clinical studies reveal loss-of-function mutation of BPTF in individuals with syndromic neurodevelopmental anomalies ( Stankiewicz et al., 2017 ). Furthermore, BPTF was recently shown to be critical for the maintenance or differentiation of mammary gland stem cells ( Frey et al., 2017 ), melanocytes ( Dar et al., 2016 , Large et al., 2016 ), and T cells ( Landry et al., 2011 , Wu et al., 2016 ). BPTF contains two motifs in its C terminus, a PHD finger and a bromodomain that bind to histone H3 lysine 4 trimethylation (H3K4me3) and histone acetylation, respectively ( Chi et al., 2010 , Ruthenburg et al., 2011 , Wysocka et al., 2006 ).…”