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

Habibe, Jayron J.; Clemente-Olivo, Maria P.; Vries, Carlie J.M. de

doi:10.3390/cells10102611

Cited by 9 publications

(6 citation statements)

References 95 publications

(131 reference statements)

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“…In our study, the methylation of the FHL2 gene was positively associated with BF. Both methylation and the expression of the FHL2 gene in the blood and adipose tissue increase with age [39]. Interestingly, hyper-methylation of FHL2 increases its expression [39].…”

Section: Discussionmentioning

confidence: 99%

“…Ranked by max R 2, these were C1S, COL11A2, Four and FHL2. Specifically, these genes are epigenetically and transcriptionally variable in adipose tissue among subjects with obesity and/or metabolic syndrome [36][37][38][39]. To visually assess the DNA methylation patterns in relation to gene expression, body fat, and age, a correlation plot between all CpGs, transcripts, body fat phenotypes, and age was generated for each gene (Figures 4-6).…”

Section: Exploring Causal Links Of Ecpgs With Adipositymentioning

confidence: 99%

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Exploring the Functional Basis of Epigenetic Aging in Relation to Body Fat Phenotypes in the Norfolk Island Cohort

Cao,

Sutherland,

Benton

et al. 2023

CIMB

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DNA methylation is an epigenetic factor that is modifiable and can change over a lifespan. While many studies have identified methylation sites (CpGs) related to aging, the relationship of these to gene function and age-related disease phenotypes remains unclear. This research explores this question by testing for the conjoint association of age-related CpGs with gene expression and the relation of these to body fat phenotypes. The study included blood-based gene transcripts and intragenic CpG methylation data from Illumina 450 K arrays in 74 healthy adults from the Norfolk Island population. First, a series of regression analyses were performed to detect associations between gene transcript level and intragenic CpGs and their conjoint relationship with age. Second, we explored how these age-related expression CpGs (eCpGs) correlated with obesity-related phenotypes, including body fat percentage, body mass index, and waist-to-hip ratio. We identified 35 age-related eCpGs associated with age. Of these, ten eCpGs were associated with at least one body fat phenotype. Collagen Type XI Alpha 2 Chain (COL11A2), Complement C1s (C1s), and four and a half LIM domains 2 (FHL2) genes were among the most significant genes with multiple eCpGs associated with both age and multiple body fat phenotypes. The COL11A2 gene contributes to the correct assembly of the extracellular matrix in maintaining the healthy structural arrangement of various components, with the C1s gene part of complement systems functioning in inflammation. Moreover, FHL2 expression was upregulated under hypermethylation in both blood and adipose tissue with aging. These results suggest new targets for future studies and require further validation to confirm the specific function of these genes on body fat regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Exploring Causal Links Of Ecpgs With Adipositymentioning

confidence: 99%

Exploring the Functional Basis of Epigenetic Aging in Relation to Body Fat Phenotypes in the Norfolk Island Cohort

Cao,

Sutherland,

Benton

et al. 2023

CIMB

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“…These fatty acids are related to retinal biology and photoreceptor renewal, and the pathway of age-related eye diseases, such as age-related macular degeneration has been studied [ 50 ]. By a comprehensive review of the FHL2 gene, relevance to various diseases was suggested [ 51 ]. ELOVL2 and FHL2 genes were used for age prediction models in saliva, buccal swab, and blood [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Integrative Approaches of DNA Methylation Patterns According to Age, Sex and Longitudinal Changes

Gim

2022

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Background: In humans, age-related DNA methylation has been studied in blood, tissues, buccal swabs, and fibroblasts, and changes in DNA methylation patterns according to age and sex have been detected. To date, approximately 137,000 samples have been analyzed from 14,000 studies, and the information has been uploaded to the NCBI GEO database. Methods: A correlation between age and methylation level and longitudinal changes in methylation levels was revealed in both sexes. Here, 20 public datasets derived from whole blood were analyzed using the Illumina BeadChip. Batch effects with respect to the time differences were correlated. The overall change in the pattern was provided as the inverse of the coefficient of variation (COV). Results: Of the 20 datasets, nine were from a longitudinal study. All data had age and sex as common variables. Comprehensive details of age-, sex-, and longitudinal change-based DNA methylation levels in the whole blood sample were elucidated in this study. ELOVL2 and FHL2 showed the maximum correlation between age and DNA methylation. The methylation patterns of genes related to mental health differed according to age. Age-correlated genes have been associated with malformations (anteverted nostril, craniofacial abnormalities, and depressed nasal bridge) and drug addiction (drug habituation and smoking). Conclusion: Based on 20 public DNA methylation datasets, methylation levels according to age and longitudinal changes by sex were identified and visualized using an integrated approach. The results highlight the molecular mechanisms underlying the association of sex and biological age with changes in DNA methylation, and the importance of optimal genomic information management.

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“…DNA methylation of FHL2 in human pancreatic islets positively correlates with its expression [5]. Several forensic studies consistently found FHL2 to be one of the DNA methylation markers that correlate most significantly with ageing [6][7][8][9].…”

Section: Introductionmentioning

confidence: 92%

Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes

et al. 2022

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Aims/hypothesis The general population is ageing, involving an enhanced incidence of chronic diseases such as type 2 diabetes. With ageing, DNA methylation of FHL2 increases, as well as expression of the four and a half LIM domains 2 (FHL2) protein in human pancreatic islets. We hypothesised that FHL2 is actively involved in glucose metabolism. Methods Publicly available microarray datasets from human pancreatic islets were analysed for FHL2 expression. In FHL2-deficient mice, we studied glucose clearance and insulin secretion. Gene expression analysis and glucose-stimulated insulin secretion (GSIS) were determined in isolated murine FHL2-deficient islets to evaluate insulin-secretory capacity. Moreover, knockdown and overexpression of FHL2 were accomplished in MIN6 cells to delineate the underlying mechanism of FHL2 function. Results Transcriptomics of human pancreatic islets revealed that individuals with elevated levels of HbA1c displayed increased FHL2 expression, which correlated negatively with insulin secretion pathways. In line with this observation, FHL2-deficient mice cleared glucose more efficiently than wild-type littermates through increased plasma insulin levels. Insulin sensitivity was comparable between these genotypes. Interestingly, pancreatic islets isolated from FHL2-deficient mice secreted more insulin in GSIS assays than wild-type mouse islets even though insulin content and islet size was similar. To support this observation, we demonstrated increased expression of the transcription factor crucial in insulin secretion, MAF BZIP transcription factor A (MafA), higher expression of GLUT2 and reduced expression of the adverse factor c-Jun in FHL2-deficient islets. The underlying mechanism of FHL2 was further delineated in MIN6 cells. FHL2-knockdown led to enhanced activation of forkhead box protein O1 (FOXO1) and its downstream genes such as Mafa and Pdx1 (encoding pancreatic and duodenal homeobox 1), as well as increased glucose uptake. On the other hand, FHL2 overexpression in MIN6 cells blocked GSIS, increased the formation of reactive oxygen species and increased c-Jun activity. Conclusions/interpretation Our data demonstrate that FHL2 deficiency improves insulin secretion from beta cells and improves glucose tolerance in mice. Given that FHL2 expression in humans increases with age and that high expression levels of FHL2 are associated with beta cell dysfunction, we propose that enhanced FHL2 expression in elderly individuals contributes to glucose intolerance and the development of type 2 diabetes. Data availability The human islet microarray datasets used are publicly available and can be found on https://www.ncbi.nlm.nih.gov/geo/. Graphical abstract

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

Cited by 9 publications

References 95 publications

Exploring the Functional Basis of Epigenetic Aging in Relation to Body Fat Phenotypes in the Norfolk Island Cohort

Exploring the Functional Basis of Epigenetic Aging in Relation to Body Fat Phenotypes in the Norfolk Island Cohort

Integrative Approaches of DNA Methylation Patterns According to Age, Sex and Longitudinal Changes

Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes

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