TY - JOUR

T1 - Structural variants in the Epb41l4a locus: TAD disruption and Nrep gene misregulation as hypothetical drivers of neurodevelopmental outcomes

AU - Salnikov, Paul

AU - Korablev, Alexey

AU - Serova, Irina

AU - Belokopytova, Polina

AU - Yan, Aleksandra

AU - Stepanchuk, Yana

AU - Tikhomirov, Savelii

AU - Fishman, Veniamin

N1 - Genetically modifed mouse generation, RNA isolation and sequencing were supported by RSCF Grant no. 22-14-00247. © 2024. The Author(s).

PY - 2024/12

Y1 - 2024/12

N2 - Structural variations are a pervasive feature of human genomes, and there is growing recognition of their role in disease development through their impact on spatial chromatin architecture. This understanding has led us to investigate the clinical significance of CNVs in noncoding regions that influence TAD structures. In this study, we focused on the Epb41l4a locus, which contains a highly conserved TAD boundary present in both human chromosome 5 and mouse chromosome 18, and its association with neurodevelopmental phenotypes. Analysis of human data from the DECIPHER database indicates that CNVs within this locus, including both deletions and duplications, are often observed alongside neurological abnormalities, such as dyslexia and intellectual disability, although there is not enough evidence of a direct correlation or causative relationship. To investigate these possible associations, we generated mouse models with deletion and inversion mutations at this locus and carried out RNA-seq analysis to elucidate gene expression changes. We found that modifications in the Epb41l4a TAD boundary led to dysregulation of the Nrep gene, which plays a crucial role in nervous system development. These findings underscore the potential pathogenicity of these CNVs and highlight the crucial role of spatial genome architecture in gene expression regulation.

AB - Structural variations are a pervasive feature of human genomes, and there is growing recognition of their role in disease development through their impact on spatial chromatin architecture. This understanding has led us to investigate the clinical significance of CNVs in noncoding regions that influence TAD structures. In this study, we focused on the Epb41l4a locus, which contains a highly conserved TAD boundary present in both human chromosome 5 and mouse chromosome 18, and its association with neurodevelopmental phenotypes. Analysis of human data from the DECIPHER database indicates that CNVs within this locus, including both deletions and duplications, are often observed alongside neurological abnormalities, such as dyslexia and intellectual disability, although there is not enough evidence of a direct correlation or causative relationship. To investigate these possible associations, we generated mouse models with deletion and inversion mutations at this locus and carried out RNA-seq analysis to elucidate gene expression changes. We found that modifications in the Epb41l4a TAD boundary led to dysregulation of the Nrep gene, which plays a crucial role in nervous system development. These findings underscore the potential pathogenicity of these CNVs and highlight the crucial role of spatial genome architecture in gene expression regulation.

KW - Humans

KW - Animals

KW - Mice

KW - Chromatin

KW - Chromosomes, Human, Pair 18

KW - Chromosomes, Human, Pair 5

KW - Databases, Factual

KW - Disease Models, Animal

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85186612868&origin=inward&txGid=41e77a415bf122db484add749de8750a

U2 - 10.1038/s41598-024-52545-y

DO - 10.1038/s41598-024-52545-y

M3 - Article

C2 - 38438377

VL - 14

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 5288

ER -