Integrated analysis reveals the alterations that LMNA interacts with euchromatin in LMNA mutation-associated dilated cardiomyopathy

Abstract

Background Dilated cardiomyopathy (DCM) is a serious cardiac heterogeneous pathological disease, which may be caused by mutations in the LMNA gene. Lamins interact with not only lamina-associated domains (LADs) but also euchromatin by alone or associates with the lamina-associated polypeptide 2 alpha (LAP2α). Numerous studies have documented that LMNA regulates gene expression by interacting with LADs in heterochromatin. However, the role of LMNA in regulating euchromatin in DCM is poorly understood. Here, we determine the differential binding genes on euchromatin in DCM induced by LMNA mutation by performing an integrated analysis of bioinformatics and explore the possible molecular pathogenesis mechanism. Results Six hundred twenty-three and 4484 differential binding genes were identified by ChIP-seq technology. The ChIP-seq analysis results and matched RNA-Seq transcriptome data were integrated to further validate the differential binding genes of ChIP-seq. Five and 60 candidate genes involved in a series of downstream analysis were identified. Finally, 4 key genes (CREBBP, PPP2R2B, BMP4, and BMP7) were harvested, and these genes may regulate LMNA mutation-induced DCM through WNT/β-catenin or TGFβ-BMP pathways. Conclusions We identified four key genes that may serve as potential biomarkers and novel therapeutic targets. Our study also illuminates the possible molecular pathogenesis mechanism that the abnormal binding between LMNA or LAP2α-lamin A/C complexes and euchromatin DNA in LMNA mutations, which may cause DCM through the changes of CREBBP, PPP2R2B, BMP4, BMP7 expressions, and the dysregulation of WNT/β-catenin or TGFβ-BMP pathways, providing valuable insights to improve the occurrence and development of DCM. Graphic abstract

Lamin A K97E leads to NF‐κB‐mediated dysfunction of inflammatory responses in dilated cardiomyopathy

“…In addition, cytokine–cytokine receptor interaction and chemokine‐mediated signaling pathways were differentially regulated. Intriguingly, this is consistent with the previous DCM‐associated transcriptome studies (Liu et al., 2021; Zhang et al., 2021). However, genes from the most strongly affected signaling pathways (IL‐17 signaling and cytokine production) were downregulated in the mutant, whereas most clinical investigations have reported elevated cytokine levels in cardiomyopathy patients (Gerbino et al., 2021).…”

Highly Specific Protein Identification by Immunoprecipitation–Mass Spectrometry Using Antifouling Microbeads

“…Both the Chromotek beads as well as the p SB- co -(aGFP) 8% beads were able to capture the three core subunits of the PRC2 complex: EED, EZH2, and SUZ12, as well as all of the other previously identified binding partners by Smits et al that occur at >0.1 stoichiometry relative to the EED bait protein: RBBP47, EZH1, JARID2, C17orf96, AEBP2, and PCL23 (Figure , green dots and labels). , With the p SB- co -(aGFP) 8% beads, three additional proteins scored just positive: LMNA, HIST1H4A, and HIST1H2BL (Figure , yellow dots and labels). The LMNA protein is, like the PRC2 complex, a chromatin regulator, , and was previously shown to also interact with one another. , The RBBP4/7 proteins operate in several protein complexes and can bind to histone H4, whereas ABP2 and JARID2 can bind to histone 2 . The PRC2 complex, the histone proteins and the LMNA proteins are thus found in close proximity to each other within the cell nucleus, and the LMNA, HIST1H4A, and HIST1H2BL proteins might in fact reflect true protein–protein interactors with the PRC2 complex (hence the labeling of these proteins in yellow).…”

“…9,49 With the pSB-co-(aGFP) 8% beads, three additional proteins scored just positive: LMNA, HIST1H4A, and HIST1H2BL (Figure 6, yellow dots and labels). The LMNA protein is, like the PRC2 complex, a chromatin regulator, 49,53 and was previously shown to also interact with one another. 54,55 The RBBP4/7 proteins operate in several protein complexes and can bind to histone H4, 56 whereas ABP2 and JARID2 can bind to histone 2.…”

Genome organization in cardiomyocytes expressing mutated A-type lamins

“…A-type lamins are mostly located at the nuclear periphery and bind LADs but a pool of these proteins can be associated with the open chromatin (euchromatin) (Gesson et al, 2014). Recently, two studies have shown an alteration of A-type lamins interaction with euchromatin in dilated cardiomyopathy (Zhang et al, 2021;Feng et al, 2022). Collectively, all these studies participate to understand the underlying mechanisms of the disease pathogenesis.…”