Biology subjects

Han, J. C.

Publications and source records attributed to Han, J. C..

7 recordsLinked to original sources

bioRxiv2026

Genetic insights on the mechanisms of human cortical folding

The unique and intricate pattern of human cortical folding is rooted in fetal neurodevelopmental processes and can now be comprehensively quantified by new neuroimaging-derived measures of sulcal complexity. Here, we provide the first genetic maps of human sulcal complexity. Beginning with large effects of rare variants, we survey nine different neurogenetic syndromes (n=615), detecting visible changes in sulcal complexity on a shared axis of sulcal change coupled to the prenatal timing of sulcation. Turning to common genetic variants, we use genome-wide association studies of complexity scores for 40 sulci in the UK Biobank (n[~]29,000) to (i) resolve variable heritability across sulci, (ii) reveal both local and remote shared genetic effects with cortical morphology, and (iii) identify complexity-associated genes and their embedding in brain maps of prenatal gene expression. These reference genetic maps uncover multiple new mechanistic pathways for cortical morphogenesis in health and disease.

neuroscience↗

bioRxiv2021

Early life energy expenditure deficits drive obesity in a mouse model of Alstrom syndrome

Alstrom syndrome (AS) is a rare multi-system disorder for which early-onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1/Alms1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on Alms1. Here, we performed comprehensive energy balance phenotyping Alms1tvrm102 mice at both eight- and eighteen-weeks-of-age. We found that adiposity gains occurred early and rapidly in Alms1tvrm102 male mice but much later in females. Rapid increases in body fat in males was due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat-diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1tvrm102 mice did not persist as mice aged, suggesting loss of Alms1 either causes a developmental delay in the mechanisms controlling early life EE, or that activation of compensatory mechanisms occurs after obesity is established. Future studies will determine how ALMS1/Alms1 modulates EE and how sex moderates this process.

physiology↗

bioRxiv2020

The gut mycobiome of healthy mice is shaped by the environment and shapes metabolic outcomes in response to diet

ObjectiveAs an active interface between the host and their diet, the gut bacteriome influences host metabolic adaptation. However, the contribution of gut fungi to host metabolic outcomes is not yet understood. Therefore, we aimed to determine if host metabolic response to an ultraprocessed diet reflects gut fungal community composition. DesignWe compared jejunal fungi and bacteria from 72 healthy mice with the same genetic background but different starting mycobiomes before and after 8 weeks on an ultra-processed or standardized diet using 16S and internal transcribed spacer region 2 ribosomal RNA sequencing. We measured host body composition using magnetic resonance imaging, examined changes in metabolically active host tissues and quantified serum metabolic biomarkers. ResultsGut fungal communities are highly variable between mice, differing by vendor, age and sex. After exposure to an ultra-processed diet for 8 weeks, persistent differences in fungal community composition strongly associate with differential deposition of body mass in male mice compared to mice on standardized diet. Fat deposition in the liver, genomic adaptation of metabolically active tissues and serum metabolic biomarkers are correlated with alterations in fungal diversity and community composition. Variation in fungi from the genera Thermomyces and Saccharomyces most strongly associate with increased weight gain. ConclusionsIn the gut of healthy mice, host-microbe metabolic interactions strongly reflect variability in fungal communities. Our results confirm the importance of luminal fungal communities to host metabolic adaptation to dietary exposure. Gut fungal communities may represent a therapeutic target for the prevention and treatment of metabolic disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/158287v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1d80579org.highwire.dtl.DTLVardef@14f5729org.highwire.dtl.DTLVardef@1e379bcorg.highwire.dtl.DTLVardef@14d2ab6_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefO_LIWhat is already known about this subject? Gut bacterial communities have evolved to influence the metabolic outcomes of the host in mammals. Evidence from across the lifespan suggests that differences in composition of these communities is associated with energy consumption. However, gut microbial communities, while often equated to bacteria, are diverse, multi-kingdom ecologies and limited information is available for the role of other kingdoms of life, such as fungi. C_LIO_LIWhat are the new findings? Gut fungal communities, collectively termed the mycobiome, are less diverse and abundant than bacterial communities in the gastrointestinal tract. This study identifies the considerable influence of the environment and dietary exposure on the composition of jejunal fungal communities in healthy mice with the same genetic background. After exposure to processed diet, differences in fungal community composition in male mice were strongly correlated with persistent differences body composition and markers of metabolic tone. C_LIO_LIHow might it impact on clinical practice in the foreseeable future? These results verify that the baseline metabolic tone of health mice strongly reflects the ecological complexity of the gastrointestinal mycobiome. Variation in the composition of gut fungal communities is likely an underappreciated source of experimental and clinical variability in metabolic studies. Gastrointestinal fungi are likely a target for prevention and treatment of metabolic disease. C_LI

microbiology↗

bioRxiv2020

Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in liver and adipose tissue

Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.

physiology↗

bioRxiv2019

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

physiology↗

bioRxiv2019

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorders anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this "transcriptional vulnerability model" by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

neuroscience↗

bioRxiv2018

In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene

Many neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus. C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A, were hyperexpressed in C11orf46-knockdown neurons. Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 protein-conjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmental periods, resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling, including up-regulated histone H3K9 methylation by the KAP1-SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is highly sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brains connectome via gene-targeted designer activators and repressor proteins.

developmental biology↗