Biology subjects

Jordan, J. M.

Publications and source records attributed to Jordan, J. M..

5 recordsLinked to original sources

bioRxiv2024

Ybx1 guides C/EBPα and cBAF chromatin-remodeling complex to promote adipogenic gene expression in steatotic hepatocytes

Excessive lipid accumulation by hepatocytes underlies the pathogenesis of metabolic-dysfunction associated steatotic liver disease (MASLD) and metabolic-dysfunction associated steatohepatitis (MASH) from the earliest stages of the disease. How liver cells regulate the commitment to storing large volumes of fat despite resulting tissue damage is not well understood. Here, we show Y box-binding protein 1 (Ybx1) is necessary for ectopic activation of an adipocyte-specific gene expression module that potentiates lipid accumulation in hepatocytes. Diet-induced obese (DIO) mice, with liver-specific depletion of Ybx1 (Ybx1LKO), are resistant to MASLD without becoming hyperlipidemic. Ybx1LKO livers exhibit upregulation of hepatocyte markers, like urea processing enzyme carbamoyl phosphate synthetase I (Cps1), and downregulation of adipocyte markers known to be transcriptionally regulated by peroxisome proliferator-activated receptor gamma (PPAR{gamma}). In nuclei of DIO mice, YBX1 interacts with CCAAT-enhancer-binding proteins alpha (C/EBP) and the canonical BRG1/BRM-associated factor complex (cBAF); and C/EBP is required for Ybx1-dependent PPAR{gamma} expression in cultured liver cells. The chromatin binding pattern of YBX1 from DIO mouse liver overlaps with those of C/EBP and cBAF at key adipogenic loci including Pparg and Cfd. However, most YBX1-DNA binding occurs on C/EBP-cBAF-depleted stretches located on chromosomes 16, 18, and 19, spanning up to five Mb, and overlapping regions which are inaccessible in differentiating preadipocytes, thereby bounding activational C/EBP-cBAF complex-DNA interactions. Moreover, YBX1 expression is increased up to nine-fold in the livers of obese patients with MASLD-MASH compared to healthy obese controls; and adipocyte-specific genes, upregulated by Ybx1, are also upregulated in human MASLD-MASH. Overall, our study uncovers Ybx1 as a critical epigenetic regulator in liver and potential therapeutic target for treatment of MASLD and MASH.

developmental biology↗

bioRxiv2019

Population selection and sequencing of C. elegans wild isolates identifies a region on chromosome III affecting starvation resistance

To understand the genetic basis of complex traits, it is important to be able to efficiently phenotype many genetically distinct individuals. In the nematode Caenorhabditis elegans, individuals have been isolated from diverse populations around the globe and whole-genome sequenced. As a result, hundreds of wild strains with known genome sequences can be used for genome-wide association studies (GWAS). However, phenotypic analysis of these strains can be laborious, particularly for quantitative traits requiring multiple measurements per strain. Starvation resistance is likely a fitness-proximal trait for nematodes, and it is related to metabolic disease risk in humans. However, natural variation in C. elegans starvation resistance has not been characterized, and precise measurement of the trait is time-intensive. Here, we developed a population selection and sequencing-based approach to phenotype starvation resistance in a pool of 96 wild strains. We used restriction site-associated DNA sequencing (RAD-seq) to infer the frequency of each strain among survivors in a mixed culture over time during starvation. We used manual starvation survival assays to validate the trait data, confirming that strains that increased in frequency over time are starvation-resistant relative to strains that decreased in frequency. These results document natural variation in starvation resistance. Further, we found that variation in starvation resistance is significantly associated with variation at a region on chromosome III. Using a near-isogenic line (NIL), we showed the importance of this genomic interval for starvation resistance. This study demonstrates the feasibility of using population selection and sequencing in an animal model for phenotypic analyses of quantitative traits, reveals natural variation of starvation resistance in C. elegans, and identifies a genomic region that contributes to such variation.

genetics↗

bioRxiv2018

Dauer diapause has transgenerational effects on starvation survival and gene expression plasticity

Phenotypic plasticity is facilitated by epigenetic regulation, and remnants of such regulation may persist after plasticity-inducing cues are gone. However, the relationship between plasticity and transgenerational epigenetic memory is not understood. Dauer diapause in Caenorhabditis elegans provides an opportunity to determine how a plastic response to the early-life environment affects traits later in life and in subsequent generations. We report that after extended diapause, post-dauer worms initially exhibit reduced reproductive success and greater inter-individual variation. In contrast, F3 progeny of post-dauers display increased starvation resistance and lifespan, revealing potentially adaptive transgenerational effects. Transgenerational effects are dependent on the duration of diapause, indicating an effect of extended starvation. In agreement, RNA-seq demonstrates a transgenerational effect on nutrient-responsive genes. Further, post-dauer F3 progeny exhibit reduced gene expression plasticity, suggesting a trade-off between plasticity and epigenetic memory. This work reveals complex effects of nutrient stress over different time scales in an animal that evolved to thrive in feast and famine.

evolutionary biology↗

bioRxiv2018

Intergenerational effects of dietary restriction on insulin/IGF signaling and reproductive development

The roundworm C. elegans transiently arrests larval development to survive extended starvation (1), but such early-life starvation reduces reproductive success (2, 3). Maternal dietary restriction (DR) buffers progeny from starvation, increasing reproductive success (4). It is unknown why early-life starvation decreases reproductive success and how maternal diet modifies this process. We show here that extended starvation in first-stage (L1) larvae followed by unrestricted feeding results in a variety of abnormalities in the reproductive system, including glp-1/Notch-sensitive germ-cell tumors and uterine masses that express neuronal and epidermal markers. We found that maternal DR reduces the penetrance of starvation-induced abnormalities, including tumors. Furthermore, we show that maternal DR reduces insulin/IGF signaling (IIS) in progeny, and that daf-16/FoxO and skn-1/Nrf, transcriptional effectors of IIS, are required in progeny for maternal DR to suppress abnormalities. daf-16/FoxO activity in somatic tissues is sufficient to suppress starvation-induced abnormalities, suggesting cell-nonautonomous regulation of reproductive system development. This work reveals complex inter- and intra-generational effects of nutrient availability mediated by IIS with consequences on developmental integrity and reproductive success.\n\nOne Sentence SummaryIntergenerational effects of diet on IIS

developmental biology↗

bioRxiv2018

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

OBJECTIVESTo conduct a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP).\n\nMETHODSAdults of European ancestry were included from 16 cohorts in Europe and North America. CBP cases were defined as those reporting back pain present for >3-6 months; non-cases were included as comparisons (\"controls\"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5x10-8. Suggestive (p<5x10-7) and genome-wide significant (p<5x10-8) variants were carried forward for replication or further investigation in an independent sample.\n\nRESULTSThe discovery sample was comprised of 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p=7.2x10-10). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3x10-11), and exceeded genome-wide significance in joint meta-analysis (0R=1.07, p=4.5x10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p=4.4x10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4x10-10).\n\nDISCUSSIONIn this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

genomics↗