Gene expression dysregulation domains are not a specific feature of Down syndrome

Ahlfors, Helena; Anyanwu, Nneka; Pakanavicius, Edvinas; Dinischiotu, Natalia; Lana-Elola, Eva; Watson-Scales, Sheona; Tosh, Justin; Wiseman, Frances K.; Briscoe, James; Page, Karen M.; Fisher, Elizabeth; Tybulewicz, Victor L. J.

doi:10.1038/s41467-019-10129-9

“…Thus, the more disconnected co-expression in low activity SLE genomes could be linked to mechanisms, with which flares occur even in patients that are in remission. Besides epigenetic phenomena, the formation of co-expression domains could occur more transiently as the result of differential expression in any given setting (32), through the clustering of differentially expressed genes, that have been spatially constrained through evolution (20,33). Such a notion is supported by our data in two ways.…”

Section: Discussionsupporting

confidence: 62%

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

Vf

¹

,

Panousis

²

,

Tektonidou

³

et al. 2020

Preprint

0

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Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. We developed a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). By implementing this method on gene expression data from a large SLE patient cohort, we identify significant diseaseassociated alterations in gene co-regulation patterns, which also correlate with the SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to DCEs of smaller size. High disease activity genomes display excessive spatial redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. Fragmentation and redistribution of gene coexpression patterns correlate with SLE-implicated biological pathways and clinically relevant endophenotypes such as kidney involvement. Notably, genes lying at the boundaries of split DCEs of low activity genomes are enriched in the interferon and other SLE susceptibility signatures, suggesting the implication of DCE fragmentation at early disease stages. Interrogation of promoter-enhancer interactions from various immune cell subtypes shows that a significant percentage of nested connections are disrupted by a DCE split or depletion in SLE genomes. Collectively, our results underlining an important role for genome organization in shaping gene expression in SLE, could provide valuable insights into disease pathogenesis and the mechanisms underlying disease flares. Significance Although widespread gene expression changes have been reported in Systemic LupusErythematosus (SLE), attempts to link gene deregulation with genome structure have been lacking. Through a computational framework for the segmentation of gene expression data, we reveal extensive fragmentation and reorganization of gene co-regulation domains in SLE, that correlates with disease activity states. Gene co-expression domains pertaining to biological functions implicated in SLE such as the interferon pathway, are being disrupted in patients, while others associated to severe manifestations such as nephritis, emerge in previously uncorrelated regions of the genome. Our results support extensive genome re-organization underlying aberrant gene expression in SLE, which could assist in the early detection of disease flares in patients that are in remission. Graphical Abstract3

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“…Besides epigenetic phenomena, the formation of co-expression domains could occur more transiently as the result of differential expression in any given setting 41 , through the clustering of differentially expressed genes, that have been positionally constrained through evolution 20,42 . Such a notion is supported by our data in two ways.…”

Section: Discussionmentioning

confidence: 99%

Extensive fragmentation and re-organization of transcription in Systemic Lupus Erythematosus

Ntasis

¹

,

Panousis

²

,

Tektonidou

³

et al. 2020

Sci Rep

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Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. In this work we propose a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). Application of this method on a large transcriptome profiling dataset of 148 SLE patients and 52 healthy individuals enabled the identification of significant disease-associated alterations in gene co-regulation patterns, which also correlate with SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to overall fewer DCEs of smaller size. High disease activity genomes display extensive redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. The dynamics of domain fragmentation and redistribution are associated with SLE clinical endophenotypes, with genes of the interferon pathway being highly enriched in DCEs that become disrupted and with functions associated to more generalized symptoms, being located in domains that emerge anew in high disease activity genomes. Our results suggest strong links between the SLE phenotype and the underlying genome structure and underline an important role for genome organization in shaping gene expression in SLE.

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“…Using our RNA sequencing data from the hippocampi of 5 WT and 5 Dp1Tyb mice aged 18.5-19 weeks 78 , we calculated the fold change in expression for the genes in the duplicated region on Mmu16 ( Lipi to Zbtb21 ), using the TPM (transcripts per million reads) measure, excluding genes whose expression summed over all 10 samples was < 1 TPM. Significantly differentially expressed genes were identified using DEseq2 79 .…”

Section: Methodsmentioning

confidence: 99%

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

Lana-Elola

¹

,

Cater

²

,

Watson-Scales

³

et al. 2021

Preprint

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Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, causative genes remain mostly unknown. Animal models enable identification of these genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. Here, we comprehensively phenotype Dp1Tyb mice and find wide-ranging DS-like phenotypes including aberrant megakaryopoiesis, reduced bone density, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for studies of many complex DS phenotypes.

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Gene expression dysregulation domains are not a specific feature of Down syndrome

Cited by 22 publications

References 40 publications

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

Extensive fragmentation and re-organization of gene co-expression patterns underlie the progression of Systemic Lupus Erythematosus

Extensive fragmentation and re-organization of transcription in Systemic Lupus Erythematosus

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

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