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Trisomy of a ‘Down syndrome critical region’ globally amplifies transcription via HMGN1 overexpression [ChIP-Seq]

ABSTRACT: Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes in cells with trisomy 21, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute per cell normalization unmasked global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulated the transcriptional changes seen with triplication of a “Down syndrome critical region” on distal chromosome 21. Absolute exogenous normalized ChIP-seq (ChIP-Rx) also revealed a global increase in histone 3 lysine 27 acetylation caused by HMGN1. Genes most amplified downstream of HMGN1 were enriched for tumor- and developmental stage-specific programs of B-cell acute lymphoblastic leukemia dependent on the 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121062 | GEO | 2018/11/13

REPOSITORIES: GEO

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Trisomy of a ‘Down syndrome critical region’ globally amplifies transcription via HMGN1 overexpression [SLAM-Seq]

Project description:Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes in cells with trisomy 21, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute per cell normalization unmasked global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulated the transcriptional changes seen with triplication of a “Down syndrome critical region” on distal chromosome 21. Absolute exogenous normalized ChIP-seq (ChIP-Rx) also revealed a global increase in histone 3 lysine 27 acetylation caused by HMGN1. Genes most amplified downstream of HMGN1 were enriched for tumor- and developmental stage-specific programs of B-cell acute lymphoblastic leukemia dependent on the 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.

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Trisomy of a ‘Down syndrome critical region’ globally amplifies transcription via HMGN1 overexpression [proB RNA-Seq]

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Transcription profiling by array of the Ts(1716)65Dn Down syndrome mouse model bone marrow lineage- c-Kit+ Sca-1+ (LSK), CMP, GMP and MEP progenitor cell populations, in which trisomy of Erg was specifically reduced to disomy using the Mld2 allele

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2015-04-15 | E-MTAB-2574 | biostudies-arrayexpress

RUNX1 isoforms in leukemogenesis

Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

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Expression profiling of human adult postmortem brain tissue from Down syndrome and healthy control subjects

Project description:Down syndrome (DS) is the result of trisomy chromosome 21 but the mechanisms by which the genotype leads to the characteristic disease phenotype are unclear. We performed a microarray study using human adult brain tissue (dorsolateral prefrontal cortex) from DS subjects and healthy controls to characterise for the first time the human adult Down syndrome brain Keywords: disease state analysis

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Correction of cognitive deficits in mouse models of Down syndrome by pharmacological inhibitor of DYRK1A

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Genome wide expression profiles in Down syndrome

Project description:Down syndrome (DS) (MIM 190685) is a complex disorder caused by the trisomy of either the entire, or a critical region of chromosome 21 (21q22.1-22.3). Despite representing the first genetic cause of mental retardation, the molecular bases of the syndrome are still largely unknown. We analyzed the genome-wide transcription profiles of lymphoblastoid cell lines (LCLs) from six DS and six euploid individuals and investigated differential gene expression and pathway deregulation associated with trisomy 21. RNA from six DS and six control LCLs was independently hybridized on the Affymetrix HU133 plus 2.0 oligonucleotide array (Affymetrix, Santa Clara, CA).The experimental design was a diseased versus control comparison. In a second approach, variability of gene expression among the DS and control group, respectively, was assessed by the analysis of the coefficient of variation (CV), calculated as the ratio between standard deviation and mean expression level for each gene among samples.

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