Biology subjects

Wayhart, J. P.

Publications and source records attributed to Wayhart, J. P..

5 recordsLinked to original sources

bioRxiv2021

Genetic, epigenetic, and environmental mechanisms govern allele-specific gene expression

Allele-specific expression (ASE) is a phenomenon where one allele is preferentially expressed over the other. Genetic and epigenetic factors cause ASE by altering the final allelic composition of a genes product, leading to expression imbalances that can have functional consequences on phenotypes. Environmental signals also impact allele-specific gene regulation, but how they contribute to this crosstalk remains understudied. Here, we explored how allelic genotype, parent-of-origin, tissue type, sex, and dietary fat simultaneously influence ASE biases in a F1 reciprocal cross mouse model. Male and female mice from a F1 reciprocal cross of the LG/J and SM/J strains were fed a high fat or low fat diet. We harnessed strain-specific variants to distinguish between two classes of ASE: parent-of-origin dependent (unequal expression based on an alleles parental origin) and sequence dependent (unequal expression based on an alleles nucleotide identity). We present a comprehensive map of ASE patterns in 2,853 genes across three metabolically-relevant tissues and nine environmental contexts. We found that both ASE classes are highly dependent on tissue type and environmental context. They vary across metabolic tissues, between males and females, and in response to dietary fat levels. Surprisingly, we found 45 genes with inconsistent ASE biases that switched direction across tissues and/or contexts (e.g. SM/J biased in one cohort, LG/J biased in another). We also integrated ASE and QTL data from populations at various degrees of intercrossing the LG/J and SM/J strains. ASE genes in these tissues are often enriched in QTLs for metabolic and musculoskeletal traits, highlighting how this orthogonal approach can prioritize candidate genes for functional validation. Together, our results provide novel insights into how genetic, epigenetic, and environmental mechanisms govern allele-specific gene regulation, which is an essential step towards deciphering the genotype to phenotype map.

genomics↗

bioRxiv2021

Parent-of-origin effects propagate through networks to shape metabolic traits

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological diseases. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of 3 imprinted and 6 non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on 2 genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high fat-fed females. Single-cell RNAseq reveals that Nnat and F2r are negatively correlated in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.

genomics↗

bioRxiv2020

Spontaneous restoration of functional β-cell mass in obese SM/J mice

Maintenance of functional {beta}-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause {beta}-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study {beta}-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and {beta}-cell function during SM/Js diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase {beta}-cell mass but not -cell mass. Obese SM/J mice do not show elevated {beta}-cell mitotic index, but rather elevated -cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that {beta}-cell mass expansion and improved {beta}-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional {beta}-cell mass can be recovered in the context of obesity.

physiology↗

bioRxiv2019

Natural brown adipose expansion and remission of hyperglycemia in obese SM/J mice

Disruption of glucose homeostasis increases the risk of type II diabetes, cardiovascular disease, stroke, and cancer. We leverage a novel rodent model, the SM/J mouse, to understand glycemic control in obesity. On a high fat diet, obese SM/J mice initially develop impaired glucose tolerance and elevated fasting glucose. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistence of obesity. A prominent phenotype is that they dramatically expand their brown adipose depots as they resolve glycemic dysfunction. This occurs naturally and spontaneously on a high fat diet, with no temperature or genetic manipulation. When the brown adipose depot is removed from normoglycemic obese mice, fasting blood glucose and glucose tolerance revert to unhealthy levels, and animals become insulin resistant. We identified 267 genes whose expression changes in the brown adipose when the mice resolve their unhealthy glycemic parameters, and find the expanded tissue has a healthier expression profile of cytokines and extracellular matrix genes. We describe morphological, physiological, and transcriptomic changes that occur during the unique brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice. Understanding this phenomenon in mice will open the door for innovative therapies aimed at improving glycemic control in obesity. Significance StatementSome obese individuals maintain normal glycemic control. Despite being obese, these individuals have low risk for metabolic complications, including type-II diabetes. If we better understood why some obese people maintain normoglycemia then we might develop new approaches for treating metabolic complications associated with obesity. However, the causative factors underlying glycemic control in obesity remain unknown. We discovered that, despite persistence of the obese state, SM/J mice enter into diabetic remission: returning to normoglycemia and reestablishing glucose tolerance and improving insulin sensitivity. A prominent phenotype is that they dramatically expand their brown adipose depots as they resolve glycemic dysfunction. Understanding this phenomenon in mice will open the door for innovative therapies aimed at improving glycemic control in obesity.

physiology↗

bioRxiv2019

Epistatic Networks Associated with Parent-of-Origin Effects on Metabolic Traits

Parent-of-origin effects (POE) are unexpectedly common in complex traits, including metabolic and neurological diseases. POE can also be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific POE on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these POE phenomena. Here, we use a simple yet powerful F1 reciprocal cross model to test the hypothesis that non-imprinted genes can generate complex POE on metabolic traits through genetic interactions with imprinted genes. Male and female mice from a F1 reciprocal cross of LG/J and SM/J strains were fed either high or low fat diets. We generated expression profiles from three metabolically-relevant tissues: hypothalamus, white adipose, and liver. We identified two classes of parent-of-origin expression biases: genes showing parent-of-origin-dependent allele-specific expression and biallelic genes that are differentially expressed by reciprocal cross. POE patterns of both gene classes are highly tissue-and context-specific, sometimes occurring only in one sex and/or diet cohort in a particular tissue. We then constructed tissue-specific interaction networks among genes from these two classes of POE. A key subset of gene pairs show significant epistasis in the F16 LG/J x SM/J advanced intercross data in cases where the biallelic gene fell within a previously-identified metabolic POE QTL interval. We highlight one such interaction in adipose, between Nnat and Mogat1, which associates with POE on multiple adiposity traits. Both genes localize to the endoplasmic reticulum of adipocytes and play a role in adipogenesis. Additionally, expression of both genes is significantly correlated in human visceral adipose tissue. The genes and networks we present here represent a set of actionable interacting candidates that can be probed to further identify the machinery driving POE on complex traits.

systems biology↗