Stem cell plasticity, acetylation of H3K14, and de novo gene activation rely on KAT7
Andrew J. Kueh,
Maria I. Bergamasco,
Anna Quaglieri,
Belinda Phipson,
Connie S.N. Li-Wai-Suen,
Ingrid M. Lönnstedt,
Yifang Hu,
Zhi-Ping Feng,
Chris Woodruff,
Rose E. May,
Stephen Wilcox,
Alexandra L. Garnham,
Michael P. Snyder,
Gordon K. Smyth,
Terence P. Speed,
Tim Thomas,
Anne K. Voss
Affiliations
Andrew J. Kueh
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
Maria I. Bergamasco
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
Anna Quaglieri
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Belinda Phipson
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3010, Australia
Connie S.N. Li-Wai-Suen
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
Ingrid M. Lönnstedt
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Yifang Hu
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Zhi-Ping Feng
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Chris Woodruff
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Rose E. May
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Stephen Wilcox
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Alexandra L. Garnham
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia
Michael P. Snyder
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Gordon K. Smyth
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia
Terence P. Speed
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3010, Australia
Tim Thomas
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Corresponding author
Anne K. Voss
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Corresponding author
Summary: In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.
