Aug 2026· International Journal of Molecular Sciences· Vol 27· 0 citations· 49 references
Medicine
TL;DR
The findings suggest that a noncoding regulatory region modulates BMSC fate and muscle growth-related processes through PENK.
Abstract
The functions of noncoding variants associated with complex traits in livestock remain poorly understood. In this study, we investigated two candidate noncoding variants within the XKR4-CHCHD7 locus identified from our previous analysis. Dual-luciferase reporter assays demonstrated allele-specific regulatory activity of these two regions in bovine muscle satellite cells (BMSCs), 293T cells, and C2C12 cells. Endogenous deletion of the candidate regions using a clustered regularly interspaced short palindromic repeats (CRISPR)-based high-fidelity Cas12Max (hfCas12Max) system revealed that the region containing chr14:22840845 (SNP-0845) exerted broader effects on BMSC function including reduced proliferation and migration, altered cell-cycle progression, and enhanced myogenic differentiation. Expression screening of candidate effector genes further identified PENK and TMEM68 as downstream candidate genes for SNP-0845. Rescue experiments further showed that PENK exerted stronger recovery effects than TMEM68 on the proliferation and migration defects caused by deletion of this region, supporting PENK as a major candidate effector downstream of the SNP-0845. Functional assays showed that PENK knockdown impaired BMSC proliferation and migration while promoting myogenic differentiation, whereas PENK overexpression partially reversed these effects. In vivo Penk knockdown reduced quadriceps femoris weight and altered muscle fiber composition in mice. Collectively, our findings suggest that a noncoding regulatory region modulates BMSC fate and muscle growth-related processes through PENK.
Findings reveal a novel epigenetic regulatory axis (novel-miR-357/S100A2 mRNA) involved in early muscle development and provide an important molecular mechanism for deeper understanding of the epigenetic regulatory processes underlying heterosis in cattle.
Gaoqing Xu, Chunqi Hou, He Ding et al.· Animal Genetics· 0 citations
It is suggested that DNMT3A may regulate rabbit growth via mediating DNA methylation of downstream genes through mediating DNA methylation of downstream genes.
Genetic variations in the low-affinity Fc Gamma Receptor (FcγR) region have been associated with various diseases and treatment efficacies. Using a high-throughput in vitro screen called Regulatory-Element Sequencing (Reel-Seq) we have identified over 400 candidate functional Single Nucleotide Polymorphisms (fSNPs) from the genomic region. In this study, we aim to identify regulatory function of these candidate non-coding fSNPs in THP-1 monocytes.
At each candidate FcγR fSNP position, we introduced random mutation in the THP-1 monocyte line using CRISPR-Cas9 based genome editing and generated over 30 knockout clones per fSNP site. We stimulated these THP-1 knockout clones with various treatments including Interferon and Lipopolysaccharide (LPS). Flow cytometry and qPCR were performed to measure the changes in cell-surface FcγR protein abundances and FcγR transcript abundances. Antibody-Dependent Cellular Phagocytosis (ADCP) assays are being conducted on selected clones to evaluate whether normal phagocytosis function has changed through the alteration of FcγR abundances.
We have observed significant changes in cell-surface FcγR abundance in these THP-1 knockout cells based on flow cytometry analysis. Detailed analysis of stimulated cells is ongoing, and we will share the full results at the meeting.
Noncoding genetic variants identified by our in vitro screen may play important roles in monocyte function, through the regulation of cell-surface FcγR abundance.
NIH NIAID #1R01AI187318-01, NCSU CVM Internal Grant 2022, CMI-EID Associate member Professional Development Scholarship 2023
Immune Response Regulation: Molecular Mechanisms (IRM)
Kaleigh Diveley, Nasif Mahmood, Xinxia Peng et al.· Journal of Immunology· 0 citations
Background: The long non-coding RNA MALAT1 is known to regulate various cellular processes; however, its role in porcine adipose tissue remains largely unexplored. Methods: In this study, we examined MALAT1 in pigs differing in fat-deposition traits by combining promoter sequencing, in silico analysis of transcription factor binding site analysis, expression profiling, and in vitro adipogenesis assays. Results: We identified three novel polymorphisms in the MALAT1 promoter regions. Several SNPs were predicted to alter binding sites for transcription factors related to metabolism and immunity, such as NFAT5, NFATC1, and BCL6B. One variant, rs329590882, differed significantly in frequency between breeds and may influence MALAT1 regulation. During adipocyte differentiation, expression of the MALAT1 isoform ENSSSCT00000080860 increased as adipogenesis progressed. Notably, this isoform was more highly expressed in lean-type Pietrain pigs than in the fatty Złotnicka Spotted (ZS) breed, suggesting that its function may not be directly related to fat accumulation. Additionally, we identified novel exon–exon junctions in MALAT1, including a junction associated with the ENSSSCT00000077869 isoform. Conclusions: These findings provide new insights into the potential role of MALAT1 in porcine adipose tissue development and immunometabolic regulation and highlight the need for improved annotation of porcine lncRNAs.
K. Piórkowska, E. Ocłoń, Ksenia Wróblewska et al.· Genes· 0 citations
These results implicate perturbed gene expression and pathways that may contribute to the severe phenotypes in LMNA-R541C and suggest several drug classes including multiple cardiac glycosides as potential targeted therapeutic candidates to be explored.
Thomas E. Keller, Ci Koehring, Brett W. Higgins et al.· bioRxiv· 0 citations
Understanding the behavior of human neural progenitor cells (NPCs) requires comparative characterization of their transcriptomic landscape, particularly through comparisons with closely related primate species. The rhesus macaque represents a key non-hominoid outgroup for such analyses, and several representative transcriptomic datasets are now available. Here, we compare genes enriched in human NPCs with those enriched in rhesus macaque NPCs and found that human NPC-enriched genes are associated with gene programs supporting radial glial identity and proliferative capacity, as well as functions related to sister chromatid segregation. This analysis identified two zinc-finger transcription factors for functional investigation: the ape-specific ZNF90 and the highly conserved OVOL2. By analysing their genome-wide binding, transcriptional output, and cellular effects in cerebral organoids, we uncovered a previously uncharacterized regulatory axis with divergent but partially overlapping effects that converge on apical progenitor (AP) maintenance. Together, our findings support a model in which lineage-specific / evolutionarily young transcription factor become integrated into a conserved developmental gene regulatory network, generating novel NPC dynamics during primate corticogenesis.
Cesar Mateo Bastidas-Betancourt, Maria Isabella Negretti-Ingravallo, İrfan Burak Göloğlu et al.· bioRxiv· 0 citations
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