title: HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development.
abstract: Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive. We report here that HoxBlinc RNA first specifies Flk1(+) mesoderm and then promotes hematopoietic differentiation through regulation of hoxb pathways. HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes. Depletion of HoxBlinc by shRNA-mediated knockdown or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxb genes and other factors regulating cardiac/hematopoietic differentiation. Reduced hoxb expression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2-b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1(+) precursors that undergo hematopoietic differentiation. Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1(+) precursors and differentiation of Flk1(+) cells into hematopoietic lineages.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Changwang
authors.initials: C
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; The Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Joonseok
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Bhavita
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Terada
authors.affiliation: Institute of Hematology, Jinan University Medical College, ShiPai, Guangzhou 510632, China.
authors.forename: Yangqiu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; The Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bungert
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; The Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA. Electronic address: qiuy@ufl.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; The Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; University of Florida Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA. Electronic address: sumingh@ufl.edu.
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D008648:Mesoderm / Q000166:cytology / Q000196:embryology*; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D009097:Multienzyme Complexes; D062085:RNA, Long Noncoding; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
keywords: HoxBlinc lincRNA; SETD1A and MLL1 HMTs; chromatin looping; hoxb gene activation; mesoderm specification