Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

Abstract

KLHL genes and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in normal cell function and in disease (KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies that examined epigenetic factors affecting transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in a super-enhancer. The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence that gene neighbors (HHATL and FBXO32) of KLHL40 and KLHL38 harbor enhancer chromatin that likely upregulates the adjacent KLHL gene. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5’ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3’ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5’ ends of genes in studies of normal and abnormal gene regulation.

Sbk2, a Newly Discovered Atrium-Enriched Regulator of Sarcomere Integrity

“…Interestingly, of the 28 cardiac-enriched low-abundance transcripts whose expression increased ≥2-fold during iAM-1 cell differentiation and decreased again ≥2-fold during subsequent dediffferentiation, >3-quarters have not been studied in the context of the heart. Among these genes, Sbk2, Doc2g, 34 and Klhl38 35 stand out for being preferentially expressed in atrial, cardiac, and striated muscle tissue, respectively. The Sbk2 gene codes for a protein kinase, which is one of the largest protein groups in eukaryotes.…”

PROTAC targeted protein degraders: the past is prologue

“…Several such E3 ligases have been identified so far. Among the clearest examples of ligases with tissue-specific expression are kelch-like family member 40 (KLHL40) and KLHL41 in skeletal muscle 145 , which have a documented role in the biology of nemaline myopathy 146 , 147 . Additionally, several central nervous system (CNS)-specific E3 ligases have emerged, such as RNF182 (ref.…”

A Pan-cancer Analysis of Kelch Like Family Member 38 (KLHL38) Alterations in Human Cancers

“…[4] It is known that KLHL proteins combine with Cullin E3 ligase to form E3 ligase complexes, which target the ubiquitination of substrate proteins. [5] There is evidence that KLHL proteins are involved in cellular oxidative stress response [6][7][8] , cell signal regulation [9,10] , cell death [11,12] , metabolism [13,14] , mitotic progression [15,16] and other essential physiological processes. Mutations, abnormal expression levels, and epigenetic disorders of the KLHL gene are responsible for hereditary diseases [17,18] , cancers [19,20] , and chronic disorders [21,22] .…”

“…KLHL38, one of the KLHL protein family members, is preferentially expressed in skeletal muscle, followed by the heart. [5] KLHL38, an atrophy reversion-related gene, has been found to be down-regulated in the Levator ani muscle after androgen treatment using an androgen deprivation model. [23] In addition, KLHL38 is highly expressed in heart tissue of heart failure patients and it leads to cardiac apoptosis by promoting ubiquitination of myocardin.…”