Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression.

Abstract

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 25 Issue 7 Pg. 1898-1911.e5 (11 13 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30428356 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• HMGN1 Protein
• Histones
• Nucleosomes
• RNA
• Lysine

Topics

• Acetylation
• Animals
• B-Lymphocytes (metabolism)
• Cell Line
• Down Syndrome (genetics)
• Genome
• HMGN1 Protein (genetics, metabolism)
• Histones (metabolism)
• Humans
• Lysine (metabolism)
• Mice, Inbred C57BL
• Models, Genetic
• Nucleosomes (metabolism)
• Phenotype
• RNA (genetics)
• Transcription, Genetic
• Transcriptome (genetics)
• Trisomy (genetics)
• Up-Regulation (genetics)