How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease.

Jayron J Habibe,Maria P Clemente-Olivo,Carlie J De Vries

doi:10.3390/cells10102611

Jayron J Habibe, Maria P Clemente-Olivo + Show 1 more

Open Access

https://doi.org/10.3390/cells10102611

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Journal: Cells	Publication Date: Oct 1, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Amsterdam University Medical Centers

Abstract

Susceptibility to complex pathological conditions such as obesity, type 2 diabetes and cardiovascular disease is highly variable among individuals and arises from specific changes in gene expression in combination with external factors. The regulation of gene expression is determined by genetic variation (SNPs) and epigenetic marks that are influenced by environmental factors. Aging is a major risk factor for many multifactorial diseases and is increasingly associated with changes in DNA methylation, leading to differences in gene expression. Four and a half LIM domains 2 (FHL2) is a key regulator of intracellular signal transduction pathways and the FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging. Remarkably, FHL2 expression increases with methylation. This was demonstrated in relevant metabolic tissues: white adipose tissue, pancreatic β-cells, and skeletal muscle. In this review, we provide an overview of the current knowledge on regulation of FHL2 by genetic variation and epigenetic DNA modification, and the potential consequences for age-related complex multifactorial diseases.

Highlights

Four and a half LIM domains 2 (FHL2) was originally described as ‘Down-regulated in Rhabdomyosarcoma LIM protein’ (DRAL) and is composed of LIM domains that are named after their initial discovery in the proteins Lin11, Isl-1 and Mec-3 [1]
An impressive number of studies have been performed to unravel the function of the protein–protein interactor FHL2 in several pathologies, ranging from cardiac dysfunction and vascular disease to cancer and obesity
As documented here, epigenetic and, to a lesser extent, genetic variation in FHL2 correlates with specific diseases and traits

Summary

Introduction

Four and a half LIM domains 2 (FHL2) was originally described as ‘Down-regulated in Rhabdomyosarcoma LIM protein’ (DRAL) and is composed of LIM domains that are named after their initial discovery in the proteins Lin, Isl-1 and Mec-3 [1]. FHL2 does not directly regulate gene expression. FHL2 is still able to regulate gene expression via interaction with transcription factors and their upstream co-regulators [4]. UHltoifwacetvoerri,al FHtraLi2tsisanodf cmoualrasdeisetsi.ll able to regulate gene expression via interaction with transcription factorsGarnodwtihnegirevuipdsetnreceamsucpop-orertgsutlhaetonrost[io4]n. The relatively high FHL2 expression in the heart explains why its function has been the subject of extensive study in this org3aonf 1. In a number of cancer cells, FHL2 protein has been described to function either as a tumor suppressor or as an oncoprotein. FHL2 plays distinct roles in breast, ovarian, and prostate cancer through its interaction and regulation of transcription factors such as the estrogen and androgen receptor [12,46,47,48,49]. The complicated role of FHL2 in cancer will not be described in further detail in this review

Regulation of FHL2 Expression by Specific Transcription Factors

FHL2 Genetic Variation

G T NA G

FHL2 SNPs in Cardiovascular Disease and Lung Inflammation

FHL2 SNPs in Coagulation and Cancer

FHL2 SNPs and Diverse Traits

Methylation of the FHL2 Gene

Hyper-Methylation of FHL2 in Aging

Hyper-Methylation of FHL2 in Metabolism

Findings

Concluding Remarks and Perspective