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Results for “Kruppel-Like Factor 4”

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PubMed2026

Establishment and longitudinal characterisation of a feeder-free embryonic stem-like cell line (ATES1) derived from blastomeres of the climbing perch, Anabas testudineus.

Embryonic stem (ES) cell-based platforms in non-model teleosts remain scarce, which may constrain in vitro studies in functional genomics and developmental biology in aquaculture-relevant species. Here, we report the derivation and characterisation of ATES1, an ES-like cell line derived from Anabas testudineus, a commercially important freshwater fish. ATES1 has been maintained for over 250 passages (> 1500 days) under feeder-free conditions in Leibovitz-15 medium supplemented with foetal bovine serum, fish serum, embryo extract, and human basic fibroblast growth factor (hbFGF). Proliferation was optimal at 28 °C, with both fish serum and hbFGF significantly enhancing cell growth. The cell line exhibited multiple characteristics associated with ES-like cells in vitro during early passages (approximately up to passages 25-35), including ES cell-like morphology, high self-renewal capacity (5-bromo-2'-deoxyuridine incorporation > 90% and a doubling time of 39.9 h), alkaline phosphatase activity, responsiveness to differentiation induction conditions, and expression of stemness-associated genes (sox2, klf4, sall4, nanog, myc). Immunocytochemistry confirmed Sox2 protein expression. However, real-time PCR revealed a significant decline in klf4 and sall4 expression, along with a lack of responsiveness to differentiation cues, increased heterogeneity, and the emergence of chromosomal abnormalities, suggesting compromised maintenance of ES-like properties during extended passaging. Despite these limitations, ATES1 remained continuously proliferative under feeder-free conditions and supported moderate to high (~ 45.8 ± 4.26%) non-viral transgene delivery efficiency via lipofection, suggesting its potential utility as a genetically manipulable in vitro system for future cellular and biotechnological applications in Anabas testudineus.

Animals↗

PubMed2026

Generation of an induced pluripotent stem cell line, LGMi002-A, from a Bardet-Biedl Syndrome patient with a BBS5 homozygous pathogenic variant.

The human induced pluripotent stem cell (iPSC) line, iPSC-BBS5stbg1, derived from a patient with a Bardet-Biedl Syndrome (BBS) phenotype and carrying a BBS5 homozygous pathogenic variant: c.123delA, p.Gly42Glufs*11 is described. The reprogramming of the patient's dermal fibroblasts was achieved using the non-integrative Sendai virus system delivering the OCT4, SOX2, KLF4 and c-MYC (OSKM) transcription factors. The established iPSC line iPSC-BBS5stbg1 displays typical iPSC morphology, maintains genomic stability, and demonstrates the ability to differentiate into cell types representative of the three embryonic germ layers. This iPSC line constitutes robust and relevant cellular model for studying BBS-associated disease mechanisms and ciliary dysfunction.

Humans↗

PubMed2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans↗

PubMed2026

Methylation-Associated Differentiation Features Define Biological and Prognostic Heterogeneity in CMS4 Colorectal Cancer.

Consensus molecular subtype 4 (CMS4) colorectal cancer (CRC) is associated with an aggressive clinical course and poor survival, yet the biological basis of heterogeneity within this subtype remains incompletely understood. DNA methylation is an epigenetic mechanism involved in transcriptional regulation, cellular differentiation, and colorectal tumorigenesis. Here, we integrated single-cell RNA sequencing (scRNA-seq), bulk data, and promoter DNA methylation data to characterize CMS4-associated cancer cell states and methylation-related features. Using the scAB algorithm, we integrated scRNA-seq with bulk CMS4 data and identified CMS4-related cells distributed across multiple patients. Single-cell analyses of cell-cell communication and transcriptional regulation revealed a CMS4-related cancer cell population characterized by macrophage migration inhibitory factor (MIF)-centered intercellular communication, enhanced caudal type homeobox 1 (CDX1) and Kruppel-like factor 5 (KLF5) regulon activity, and gene modules enriched in differentiation-related pathways. CytoTRACE analysis further stratified CMS4 cancer cells into poorly and well-differentiated states, yielding 802 differentially expressed genes (DEGs). Linking these differentiation-associated DEGs with bulk expression and promoter methylation data identified 218 methylation-associated DEGs showing significant inverse methylation expression correlations, suggesting a link between differentiation-related heterogeneity and promoter methylation. Univariable Cox regression followed by LASSO regression further prioritized eight genes for construction of the methylation and differentiation-related prognostic model (MeDiff-PM). MeDiff-PM consistently stratified overall survival in the TCGA CMS4 cohort and two independent validation cohorts, with cutoff-independent continuous Cox analyses further supporting its prognostic association across cohorts. And MeDiff-PM remained prognostically significant after adjustment for available clinical variables. High MeDiff-PM risk scores were associated with activation of P53, WNT, and ubiquitin-mediated proteolysis pathways and with consistent predicted drug response differences for compounds across three CMS4 cohorts. While individual in silico knockout analysis suggested links between MeDiff-PM genes and metallothionein-related and immune-associated transcriptional responses. Collectively, these findings indicate that methylation-associated differentiation features represent a molecular dimension of intra-CMS4 heterogeneity and provide a biologically informed framework for prognostic stratification within CMS4 CRC.

Humans↗

PubMed2025

Genomic loci and molecular genetic mechanisms for hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a common, chronic and debilitating inflammatory disease that most commonly affects intertriginous skin. Despite its high heritability, the genetic underpinnings of HS remain poorly understood. OBJECTIVES: To identify genetic signals associated with HS, determine genetic relationships with other diseases and investigate potential molecular genetic mechanisms. METHODS: We performed a genome-wide association meta-analysis of six studies, totalling 4540 patients with HS and > 1 million control participants, and identified genetic correlations with other common diseases. We integrated the HS data with expression quantitative trait loci from 10 trait-relevant tissues, epigenomic and transcriptomic data from human scalp, differential expression data from HS lesions vs. adjacent skin and mesenchymal Hi-C chromatin looping data. To identify functional noncoding variants, we performed transcriptional reporter assays for signals near KLF5 and SOX9. RESULTS: We identified 11 significant HS signals across 7 loci: 4 corresponded to previously reported associations, 4 represented novel signals within known loci and 3 were signals in newly implicated loci. We identified significant genetic correlations between HS and other inflammatory conditions, particularly inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes mellitus and asthma. We prioritized candidate genes for the 11 signals. The risk allele at KLF5 exhibited 10-fold greater transcriptional activity than the nonrisk allele, while risk alleles at SOX9 showed significantly reduced transcriptional activity. CONCLUSIONS: Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.

Humans↗