Biology subjects

Dykxhoorn, D.

Publications and source records attributed to Dykxhoorn, D..

3 recordsLinked to original sources

bioRxiv2026

Enhanced Hi-C Capture Analysis reveals complex regulatory architecture at the PICALM-EED locus for Alzheimer Disease

ObjectiveBoth the phosphatidylinositol binding clathrin assembly protein gene (PICALM) and the embryonic ectoderm development gene (EED) have been implicated as causal genes driving a genome-wide association for Alzheimer disease (AD) risk. We employed a new virtual approach using genome-wide chromatin interactions (Hi-C) called enhanced Hi-C Capture Analysis (eHiCA) to identify the genes and regulatory regions that are driving this important AD risk association. MethodsHi-C data from the frontal cortex of eight AD patients, as well as inducible pluripotent stem cell-derived microglia and spheroids of AD and control patients were used. We applied 14 eHiCA baits each containing a GWAS SNP to identify the cis regulatory interactions in this GWAS locus at a 5kb resolution. ResultsThe baits derived from the GWAS associated haplotype primarily interacted with the PICALM promoter and the large cis-regulatory elements cluster (CREe) lying upstream of the EED promoter. The EED promoter interacts with PICALM gene body and promoter region but not directly with the associated risk haplotype. Although the AD-associated variants segregate together as a haplotype in the population, each bait exhibited distinct functional chromatin interactions. InterpretationThe PICALM gene is the primary driver of the association in microglia along with the CREe locus. Different SNPs in a segregating haplotype can display different physical Hi-C interactions. This study demonstrates that eHiCA can help resolve the casual genes driving complex GWAS associations, opening new pathways to study Alzheimer disease and other disorders.

genomics↗

bioRxiv2022

The Growth Hormone Releasing Hormone Signaling Pathway Governs Cardiomyocyte differentiation in human iPS cells.

Here, we present an O2-independent/HIF-1 (Hypoxia inducible factor-1)-dependent mechanism that regulates developmental and regenerative growth of mammalian cardiomyoblasts. An autocrine feedback mechanism of GH/IGF1/SST (Growth hormone/Insulin-like growth factor 1/Somatostatin) signaling, mediated by GHRH/GHRH-R (Growth hormone-releasing hormone/GHRH-Receptor), is established specifically in NKX2-5 (NK2 Homeobox 5) expressing myocardial cells which affects HIF-1 stability through cAMP (cyclic adenosine monophosphate) or cGMP (cyclic guanosine monophosphate) activity. cAMP-mediated HIF-1 stabilization fuels Warburg metabolism and enhances NKX2-5 expression, limiting the developmental and regenerative growth of cardiomyoblasts. In contrast, cGMP-mediated HIF- 1 inhibition (or knock-out of HIF-1) redirects glycolytically derived citrate toward long-chain saturated fatty acid biosynthesis, leading to enhanced developmental and regenerative growth of cardiomyoblasts. These findings suggest that HIF1-mediated glycolysis serves as a rate-limiting, O2-independent sensor of cardiomyogenesis and that targeting GHRH/GHRH-R signaling could be a therapeutic strategy for regenerating the mammalian heart post-injury. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/478572v3_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@16d3f74org.highwire.dtl.DTLVardef@16115edorg.highwire.dtl.DTLVardef@e68dc7org.highwire.dtl.DTLVardef@660861_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOSummary Figure.C_FLOATNO Cardiomyoblast proliferative capacity is regulated by HIF1-mediated metabolic profile, through an NKX2-5 lineage-specific, O2-independent feedback mechanism. (A), HIF-1 is aerobically regulated through the intracellular activation of cAMP and cGMP in response to a GH1/IGF1/SST feedback mechanism, which activates the GHRH/GHRH-R signaling pathway in NKX2-5+ cardiomyoblasts. Stabilized HIF-1 (e.g. by CoCl2) promotes Warburg metabolism and cell cycle exit, whereas knockout or inhibition (e.g. YC-1) of HIF-1 or cAMP (low-dose metformin) promotes de novo fatty acid synthesis and enhances cardiomyoblast proliferation. (B), HIF-1 aerobic stabilization switches the metabolism towards glycolysis and restricts cardiomyoblast proliferation. Contrariwise, knockout of HIF-1 promotes oxidative metabolism in the Krebs cycle rather than lactate synthesis, thus stimulating the proliferative and regenerative capacity of cardiomyoblasts. C_FIG

cell biology↗

bioRxiv2020

βPix sequesters IDOL and prevents LDL receptor degradation through a β2AR-regulated signaling pathway in Alport Syndrome

Alport syndrome (AS) is a rare disease of the glomerular basement membrane type IV collagen causing progressive renal failure. We reported increased accumulation of low-density lipoprotein (LDL) receptor (LDLR) and subsequent LDL cholesterol (LDL-C) uptake in renal tubular epithelial cells (TEC) in Alport mice, but the mechanisms regulating LDLR stability and function remain unknown. Here, we show that a selective {beta}2-Adrenoceptor ({beta}2AR) agonist, salbutamol, decreased LDLR levels and LDL-C uptake in Alport kidneys accompanied with reduced albuminuria and improved cardiac systolic and diastolic function. Similarly, salbutamol decreased LDL-C uptake in HK2 and HEK293 human renal epithelial cell lines, in smooth muscle cells from an X-linked hereditary nephropathy dog model (a large animal model of AS), and in TECs differentiated from AS patient-derived iPSCs. We show that the Rac1/Cdc42 guanine nucleotide exchange factor {beta}1Pix blocked {beta}2AR-induced LDLR degradation and, hence, increased LDL-C uptake. {beta}1Pix also abrogated ubiquitination and degradation of LDLR induced by the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase that promotes lysosomal LDLR ubiquitination and degradation. We identify a multimolecular complex comprised of {beta}Pix, IDOL, and LDLR and demonstrate that {beta}Pix counteracts {beta}2AR-mediated LDLR degradation by sequestering IDOL. Our findings show {beta}Pix acts as a significant post-transcriptional regulator of IDOL-mediated LDLR degradation and identify {beta}2AR activation as a potential treatment for Alport pathology.

molecular biology↗