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Modular Transcriptional Repertoire and microRNA target Analyses Characterize Genomic Dysregulation in the Thymus of Down Syndrome Infants

ABSTRACT: Trisomy 21- driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and microRNA-target analyses. We used whole thymic tissue (corticomedullar sections) - obtained at heart surgery from Down syndrome (DS) and karyotipically normal individuals (CT) - and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires and the interactions between all the system’s constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS gene networks corresponded to sub-network changes, i.e. module (communities) changes. Distinct communities of highly interconnected gene sets were topologically identified for DS and CT networks. The role of microRNAs in modulating the expression of highly connected genes in CT and DS was revealed through microRNA-target analysis. Trisomy 21 gene dysregulation in thymus may well be depicted as the breakdown and altered reorganization of transcriptional modules.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70573 | GEO | 2017/02/09

SECONDARY ACCESSION(S): PRJNA289052

REPOSITORIES: GEO

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Modular Transcriptional Repertoire and microRNA-target Analyses in Thymic Tissue of Down Syndrome Infants

Project description:Trisomy 21- driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and microRNA-target analyses. We used whole thymic tissue (corticomedullar sections) - obtained at heart surgery from Down syndrome (DS) and karyotipically normal individuals (CT) - and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires and the interactions between all the system’s constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS gene networks corresponded to sub-network changes, i.e. module (communities) changes. Distinct communities of highly interconnected gene sets were topologically identified for DS and CT networks. The role of microRNAs in modulating the expression of highly connected genes in CT and DS was revealed through microRNA-target analysis. Trisomy 21 gene dysregulation in thymus may well be depicted as the breakdown and altered reorganization of functional modules.

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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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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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Trisomy of a ‘Down syndrome critical region’ globally amplifies transcription via HMGN1 overexpression [NALM6 RNA-Seq]

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

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Project description:In this study we performed a systematic analysis of the non-coding RNA (ncRNA) transcriptomes of the Down Syndrome (DS) developing hippocampus using the DS mouse model Dp16(1)Yey. DS, caused by the trisomy of chromosome 21 (HSA21) is the most frequent human chromosomal disorder. Hippocampal-dependent learning and memory impairment is one of the most significant deficits of DS. ncRNAs: microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) have been increasingly revealed to be participating in various biological activities, especially in the brain development and neuronal functions. This study provides a map of the dysregulated lncRNAs and circRNAs in the DS developing hippocampus for the first time.

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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.

2023-05-10 | PXD030616 | Pride

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

Project description:Down Syndrome (DS) results from the trisomy of human chromosome 21 (HSA21). It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Among candidate genes explaining intellectual disabilities seen in DS patients, the dual specificity tyrosine-phosphorylation regulated kinase 1A, DYRK1A, is located in the DS critical region of chromosome 21. DYRK1A has become a major screening target for the development of selective and potent pharmacological inhibitors. We here investigated the effects of a relatively selective DYRK1A inhibitor, Leucettine 41 (hereafter L41) in three different trisomic mouse models with increasing genetic complexity, Tg(Dyrk1a), Ts65Dn and Dp1Yey. Leucettines are derived from the marine sponge alkaloid Leucettamine B.

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Identification of dysregulated genes in lymphocytes from children with Down syndrome

Project description:The aim of this study was to analyze global changes of gene expression in lymphocytes from children with trisomy 21 by means of the serial analysis of gene expression (SAGE) methodology. Comparison between DS and normal profiles revealed that most of the transcripts were expressed at similar levels. Among the 242 significantly differentially expressed SAGE tags, many of them corresponded to genes involved in transcription, RNA processing, signaling, immune response and lipid metabolism. Our results indicate that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS. Keywords: SAGE analysis in normal and Down syndrome lymphocytes Lymphocytes were isolated from peripheral blood of normal and karyotypically confirmed full trisomy 21 children. Children included in the study, ranging in age from 1-4 years, were self reported as free of chronic or acute infections. Total RNA was isolated with TRIzol reagent (Invitrogen). The SAGE libraries were constructed using pooled RNA from six DS children (DS library) and six normal children (control group) to eliminate any individual variation. SAGE was performed by means of the I-SAGE kit (Invitrogen) following the manufacturer’s instructions.

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