Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression
Cody T. Mowery,
Jaime M. Reyes,
Lucia Cabal-Hierro,
Kelly J. Higby,
Kristen L. Karlin,
Jarey H. Wang,
Robert J. Kimmerling,
Paloma Cejas,
Klothilda Lim,
Hubo Li,
Takashi Furusawa,
Henry W. Long,
David Pellman,
Bjoern Chapuy,
Michael Bustin,
Scott R. Manalis,
Thomas F. Westbrook,
Charles Y. Lin,
Andrew A. Lane
Affiliations
Cody T. Mowery
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Jaime M. Reyes
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Lucia Cabal-Hierro
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Kelly J. Higby
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Kristen L. Karlin
Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA
Jarey H. Wang
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
Robert J. Kimmerling
Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
Paloma Cejas
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Klothilda Lim
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Hubo Li
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Takashi Furusawa
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA
Henry W. Long
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
David Pellman
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
Bjoern Chapuy
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Michael Bustin
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA
Scott R. Manalis
Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
Thomas F. Westbrook
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Charles Y. Lin
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA
Andrew A. Lane
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Corresponding author
Summary: Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted. : How trisomy 21 contributes to Down syndrome phenotypes, including increased leukemia risk, is not well understood. Mowery et al. use per-cell normalization approaches to reveal global transcriptional amplification in Down syndrome models. HMGN1 overexpression is sufficient to induce these alterations and promotes lineage-associated transcriptional programs, signaling, and B cell progenitor phenotypes. Keywords: Down syndrome, leukemia, HMGN1, spike-in normalization, RNA sequencing, ChIP-Rx, transcriptional amplification, trisomy 21, Down syndrome critical region, DSCR, B cells
