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Noncoding variation near UBE2E2 orchestrates cardiometabolic pathophenotypes through polygenic effectors.

Yang Zhang1,2,3, Natalie L David2, Tristan Pesaresi2,3

  • 1School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China.

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|December 10, 2024
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Summary
This summary is machine-generated.

Genetic variations in noncoding DNA can influence complex diseases like type 2 diabetes by affecting multiple genes. This study reveals polygenic regulatory effects, where variants impact distant genes, contributing to disease mechanisms.

Keywords:
Adipose tissueDiabetesEndocrinologyGenetic variationGenetics

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Area of Science:

  • Genetics
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Genome-wide association studies (GWAS) identify genetic variants linked to complex diseases, but underlying mechanisms, especially for noncoding variations, are often unclear.
  • Type 2 diabetes mellitus (T2D) and visceral adiposity involve complex genetic factors and tissue-specific mechanisms.
  • Understanding noncoding variation's role in T2D pathogenesis is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the functional impact of noncoding single nucleotide variants (SNVs) associated with T2D and visceral adiposity at the UBE2E2 locus.
  • To identify candidate cis-regulatory elements and causal genes influenced by these noncoding SNVs.
  • To elucidate the polygenic regulatory effects of noncoding variation in metabolic disease.

Main Methods:

  • CRISPR targeting of SNV-containing regions and CRISPR interference (CRISPRi) screening to identify regulatory elements.
  • Genetic loss-of-function studies in murine models of diet-induced obesity.
  • Ex vivo adipogenesis assays to assess the impact on fat cell differentiation.
  • Integration of genetic and functional genomics approaches.

Main Results:

  • Noncoding variants at the UBE2E2 locus influenced the regulation of multiple genes, including UBE2E2, UBE2E1, and neighboring genes.
  • Targeting multiple genes near UBE2E2 attenuated adipogenesis in vitro.
  • Compound heterozygous loss of function for Ube2e2 and Ube2e1 in mice better replicated pathological adiposity and metabolic phenotypes than homozygous loss of either gene alone.
  • Regulatory effects of noncoding variation extended beyond the nearest gene.

Conclusions:

  • Noncoding variants can exert polygenic regulatory effects, influencing multiple genes and contributing to complex diseases like T2D.
  • Pathogenic mechanisms in T2D may involve coordinated regulation of multiple genes by noncoding variation.
  • This study provides a model for understanding how distal noncoding variation drives complex disease phenotypes.