title: An MLL-dependent network sustains hematopoiesis.
abstract: The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll-dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll-dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll-deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia.
authors.affiliation: Department of Genetics , Institute for Quantitative Biomedical Sciences, and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Artinger
authors.forename: Bibhu P
authors.initials: BP
authors.lastname: Mishra
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Zaffuto
authors.forename: Bin E
authors.initials: BE
authors.lastname: Li
authors.forename: Elaine K Y
authors.initials: EK
authors.lastname: Chung
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Moore
authors.forename: Yufei
authors.initials: Y
authors.lastname: Chen
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
mesh_terms: D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology
chemical_list: C497422:KMT2A protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: HSC; epigenetics; proliferation