title: USF1 and hSET1A mediated epigenetic modifications regulate lineage differentiation and HoxB4 transcription.
abstract: The interplay between polycomb and trithorax complexes has been implicated in embryonic stem cell (ESC) self-renewal and differentiation. It has been shown recently that WRD5 and Dpy-30, specific components of the SET1/MLL protein complexes, play important roles during ESC self-renewal and differentiation of neural lineages. However, not much is known about how and where specific trithorax complexes are targeted to genes involved in self-renewal or lineage-specification. Here, we report that the recruitment of the hSET1A histone H3K4 methyltransferase (HMT) complex by transcription factor USF1 is required for mesoderm specification and lineage differentiation. In undifferentiated ESCs, USF1 maintains hematopoietic stem/progenitor cell (HS/PC) associated bivalent chromatin domains and differentiation potential. Furthermore, USF1 directed recruitment of the hSET1A complex to the HoxB4 promoter governs the transcriptional activation of HoxB4 gene and regulates the formation of early hematopoietic cell populations. Disruption of USF or hSET1A function by overexpression of a dominant-negative AUSF1 mutant or by RNA-interference-mediated knockdown, respectively, led to reduced expression of mesoderm markers and inhibition of lineage differentiation. We show that USF1 and hSET1A together regulate H3K4me3 modifications and transcription preinitiation complex assembly at the hematopoietic-associated HoxB4 gene during differentiation. Finally, ectopic expression of USF1 in ESCs promotes mesoderm differentiation and enforces the endothelial-to-hematopoietic transition by inducing hematopoietic-associated transcription factors, HoxB4 and TAL1. Taken together, our findings reveal that the guided-recruitment of the hSET1A histone methyltransferase complex and its H3K4 methyltransferase activity by transcription regulator USF1 safeguards hematopoietic transcription programs and enhances mesoderm/hematopoietic differentiation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Changwang
authors.initials: C
authors.lastname: Deng
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Shermi
authors.initials: S
authors.lastname: Liang
authors.forename: Kairong
authors.initials: K
authors.lastname: Cui
authors.forename: Tal
authors.initials: T
authors.lastname: Salz
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Tang
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.forename: Robert
authors.initials: R
authors.lastname: Roeder
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: Jörg
authors.initials: J
authors.lastname: Bungert
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051720:Upstream Stimulatory Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins; D008780:Methyltransferases; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; C090460:HOXB4 protein, human; C497181:USF1 protein, human; C067143:TAL1 protein, human; C526068:Setd1A protein, human