title: Analysis of Mll1 deficiency identifies neurogenic transcriptional modules and Brn4 as a factor for direct astrocyte-to-neuron reprogramming.
abstract: BACKGROUND
  Mixed lineage leukemia-1 (Mll1) epigenetically regulates gene expression patterns that specify cellular identity in both embryonic development and adult stem cell populations. In the adult mouse brain, multipotent neural stem cells (NSCs) in the subventricular zone generate new neurons throughout life, and Mll1 is required for this postnatal neurogenesis but not for glial cell differentiation. Analysis of Mll1-dependent transcription may identify neurogenic genes useful for the direct reprogramming of astrocytes into neurons.
  
  
  OBJECTIVE
  To identify Mll1-dependent transcriptional modules and to determine whether genes in the neurogenic modules can be used to directly reprogram astrocytes into neurons.
  
  
  METHODS
  We performed gene coexpression module analysis on microarray data from differentiating wild-type and Mll1-deleted subventricular zone NSCs. Key developmental regulators belonging to the neurogenic modules were overexpressed in Mll1-deleted cells and cultured cortical astrocytes, and cell phenotypes were analyzed by immunocytochemistry and electrophysiology.
  
  
  RESULTS
  Transcriptional modules that correspond to neurogenesis were identified in wild-type NSCs. Modules related to astrocytes and oligodendrocytes were enriched in Mll1-deleted NSCs, consistent with their gliogenic potential. Overexpression of genes selected from the neurogenic modules enhanced the production of neurons from Mll1-deleted cells, and overexpression of Brn4 (Pou3f4) in nonneurogenic cortical astroglia induced their transdifferentiation into electrophysiologically active neurons.
  
  
  CONCLUSIONS
  Our results demonstrate that Mll1 is required for the expression of neurogenic but not gliogenic transcriptional modules in a multipotent NSC population and further indicate that specific Mll1-dependent genes may be useful for direct reprogramming strategies.
authors.affiliation: *Department of Neurological Surgery, ‡The Eli and Edythe Broad Institute of Regeneration Medicine and Stem Cell Research, §Department of Pathology, and ¶Department of Neurology University of California, San Francisco, San Francisco, California; and ‖Surgical Service, San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Potts
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Siu
authors.forename: James D
authors.initials: JD
authors.lastname: Price
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Salinas
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Cho
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Ramos
authors.forename: Junghyun
authors.initials: J
authors.lastname: Hahn
authors.forename: Marta
authors.initials: M
authors.lastname: Margeta
authors.forename: Michael C
authors.initials: MC
authors.lastname: Oldham
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D054338:Cell Transdifferentiation / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D046228:Microarray Analysis; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D050809:POU Domain Factors / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; C074067:Pou3f4 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse