Biology subjects

Yi, D.

Publications and source records attributed to Yi, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Macroscale traveling waves link perception, response selection, and vocal production during marmoset vocal interactions

Vocal communication involves a series of cognitive processes, which can be broadly categorized into three components: perceiving communicative signals; deciding whether and how to respond; and generating vocal motor output. These processes must work harmoniously, with integration and bridging between components being crucial for effective communication. Previous research on vocal communication has typically focused on specific brain regions or isolated cognitive functions, often lacking a holistic perspective of macro-scale, whole-cortical dynamics and their role in the complete communication process. Therefore, although the cortical areas associated with each cognitive component have been localized in humans, the macro-scale cortical dynamics underlying the integration of these cognitive processes remain unknown. Building on recent findings linking macro-scale cortical dynamics to behavioral performance, we hypothesized that traveling wave like cross-areal interactions play a role in integrating the three communicative components. To test this hypothesis, we recorded whole-cortical activity using epidural electrocorticography (ECoG) while subject marmosets vocally interacted with partners. We found theta-band activation in several cortical areas, including the parietal and auditory cortices, while listening to partners calls. This activity was further modulated depending on whether the subjects engaged in vocal interactions, potentially representing the transformation of sensory processing into decision-making and vocal motor preparation. Given the widespread nature of this modulation, we next characterized whole-brain activity patterns by employing a novel analytical method, Weakly Orthogonal Conjugate Contrast Analysis (WOCCA). This analysis revealed that cortical activity could be decomposed into two distinct traveling wave like propagation patterns, a rotational and a translational wave, and both waves discriminated communicative conditions consistent with localized activity. The rotational wave further represented vocal motor preparation through trigger-like temporal pattern. In addition, the magnitude of the translational wave immediately before subjects vocal production correlated with the vocal production-induced suppression of high-gamma-band activity, particularly in the prefrontal and auditory cortices. As vocalization-induced suppression is believed to reflect sensory prediction, the translational wave may propagate specific decision-related or acoustic information necessary for subsequent vocal production to local cortical areas. These findings suggest that the brain orchestrates the sequential cognitive processes underlying vocal communication through macro-scale traveling waves.

neuroscience↗

bioRxiv2026

Multi-Layer Brain-Mimicking Phantom for Replicating Dura and Pia Membrane Dimpling and Rupture Properties During Neural Interface Implantation

Development of novel neural interfaces faces buckling challenges and heavily relies on trial-and-error tests via in vivo animal brain insertions for design optimizations towards the minimal-damaging version for enhanced recording and stimulation outcome. To enable low-cost and fast-turnaround neural interface development and to enable previously impossible insertions via new understanding of the cutting process, this study developed a reproducible, multi-layer brain-mimicking phantom designed to replicate the rodent pia and dura mater dimpling and rupture force performance observed during in vivo tests. The phantom was composed of a 0.5% (w/v) agarose cortex layer, a 1.01% (w/v) agarose pia mater layer, and a pre-stretched polyvinyl chloride (PVC) dura mater layer, assembled via easily duplicable benchtop protocols. Using a cantilever-beam force measurement system, rupture force and dimpling depth were quantified across microwires of varying diameters (12-100 m), materials (tungsten, stainless steel), and tip geometries, as well as segmented silicon probe shanks. Phantom test results closely matched in vivo Sprague-Dawley rat data, validating the performance of the developed multi-layer phantom. At the same time, phantom insertion trial variability was substantially lower than in vivo tests, enabling a repeatable, low-cost, early-stage screening platform of novel electrode designs. The phantoms modular design also allowed tuning of layer thickness and stifness of each layer for diferent species or devices, ofering a validated customizable testing platform to accelerate novel neural implant development and reduce animal use.

neuroscience↗

bioRxiv2024

Enhanced endogenous gene tagging in human induced pluripotent stem cells via AAV6-mediated donor delivery

Systematically tagging endogenous proteins with fluorescent markers in human induced pluripotent stem cells (hiPSCs) allows observation of live cell dynamics in different cell states. However, the precise insertion of fluorescent proteins into live cells via CRISPR/Cas9-induced editing relies on homology-directed repair (HDR). The nonhomologous end-joining (NHEJ) DNA repair pathway often outcompetes HDR, resulting in irreversible insertions and deletions (INDELs) and low knock-in efficiency. Recognizing successful HDR-mediated tagging events is an additional challenge when the target gene is not expressed in stem cells and successful tagging cannot be immediately observed. To address these challenges, we used: 1) adeno-associated virus serotype 6 (AAV6) mediated DNA donors at optimized multiplicity of infection (MOI) to deliver tag payloads at maximal efficiency; 2) titrated, multiplexed Cas9:gRNA ribonucleo-protein (RNP) amounts to assure balanced HDR/INDEL frequency among conditions; 3) long-amplicon droplet digital PCR (ddPCR) to measure the frequency of HDR-generated alleles in edited pools; and 4) simultaneous Inference of CRISPR Edits (ICE) to detect and thereby avoid conditions significantly saturated (>50%) with INDELs. These approaches enabled us to identify efficient and accurate editing conditions and recover tagged cells, including cells tagged at loci not expressed in stem cells. Together these steps allowed us to develop an efficient methodology and workflow to clonally isolate directly from an ideal cell pool with optimal HDR and minimized INDEL frequencies. Using this approach, we achieved both monoallelic and biallelic insertion of fluorescent markers into four genes that are turned on during differentiation but not initially expressed in hiPSCs, where direct selection of tagged cells based on fluorescence was impossible: TBR2, TBXT, CDH2 (pro-differentiation and pro-migratory genes), and CDH5 (endothelial specific gene). Through a systematic evaluation of various gRNA sequences and RNP concentrations, we identified conditions for each gene that achieved high HDR frequencies, peaking at 38.6%, while also avoiding conditions saturated with INDELs, where isolation of clones with a tagged allele in trans with an unedited allele is difficult. Over-all, this methodology enhances the efficiency of fluorescent tag knock-in at genes not expressed in hiPSCs, facilitating reliable image-based observation of cellular processes, and enables recovery of accurately edited mono- and biallelically tagged clones. We standardized these approaches to yield an efficient and general workflow for introducing large HDR mediated knock-ins into hiPSCs.

cell biology↗

bioRxiv2024

General Capillary Endothelial Cells Undergo Reprogramming into Arterial Endothelial Cells in Pulmonary Hypertension through HIF-2a/Notch4 Pathway

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of distal capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our recent single-cell RNA sequencing, spatial transcriptomics analysis, RNASCOPE, and immunostaining analysis showed that arterial ECs accumulation and loss of capillary ECs were evident in human PAH patients and pulmonary hypertension (PH) rodents. Pseudotime trajectory analysis of the single-cell RNA sequencing data suggest that lung capillary ECs transit to arterial ECs during the development of PH. Our study also identified CXCL12 as the marker for arterial ECs in PH. Capillary EC lineage tracing approach using capillary specific-Dre;Tdtomato reporter mice demonstrated that capillary ECs gave rise to arterial ECs during PH development. Genetic deletion of HIF-2a or pharmacological inhibition of Notch4 normalized the arterial programming in PH. In conclusion, our study demonstrates that capillary endothelium transits to arterial endothelium through the HIF-2a-Notch4 pathway during the development of PAH. Thus, targeting arterial EC transition might be a novel approach for treating PAH patients.

physiology↗

bioRxiv2024

Scalable and Efficient Generation of Mouse Primordial Germ Cell-like Cells

Primordial germ cells (PGCs) are the founder cells of the germline. The ability to generate PGC-like cells (PGCLCs) from pluripotent stem cells has advanced our knowledge of gametogenesis and holds promise for developing infertility treatments. However, generating an ample supply of PGCLCs for demanding applications such as large-scale genetic screens has been a limitation. Here, we demonstrated that simultaneous overexpression of 4 transcriptional factors - Nanog and three PGC master regulators Prdm1, Prdm14 and Tfap2c - in suspended mouse epiblast like cells (EpiLCs) and formative embryonic stem cells (ESCs) results in efficient and cost-effective production of PGCLCs. Nanog overexpression enhanced the PGC regulatory network, suppressed differentiation of somatic lineages, and maintained PGC fate. PGCLCs generated in this manner have transcriptomes similar to in vivo PGCs and are more advanced than cytokine-induced PGCLCs. These differentiated PGCLCs could be sustained over prolonged periods of culture and could differentiate into spermatogonia-like cells in vitro. We exploited this platform to conduct a bulk epigenome-wide CRISPRi screen to identify genes that decreased the efficiency of PGCLC formation when downregulated. One of the identified candidates was Ncor2, a transcriptional repressor that acts via recruitment of Class I and Class IIa histone deacetylases (HDACs). Consistently with this finding, the HDAC inhibitors valproic acid (VPA; an anti-convulsant) and sodium butyrate (SB; a widely-used dietary supplement) suppressed PGCLC differentiation. Furthermore, exposure of developing mouse embryos to SB or VPA caused hypospermatogenesis. This work demonstrates the feasibility of this platform to efficiently conduct large-scale functional screens of genes, chemicals, or other agents that may impact germline development.

cell biology↗

bioRxiv2024

Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/-, TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2 expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

molecular biology↗

bioRxiv2023

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension

RationaleRare genetic variants and genetic variation at loci in an enhancer in SRY-Box Transcription Factor 17 (SOX17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutation in SOX17 in PAH pathogenesis has not been reported. ObjectivesTo investigate the role of SOX17 deficiency in pulmonary hypertension (PH) development. MethodsHuman lung tissue and endothelial cells (ECs) from IPAH patients were used to determine the expression of SOX17. Tie2Cre-mediated and EC-specific deletion of Sox17 mice were assessed for PH development. Single-cell RNA sequencing analysis, human lung ECs, and smooth muscle cell culture were performed to determine the role and mechanisms of SOX17 deficiency. A pharmacological approach was used in Sox17 deficiency mice for therapeutic implication. Measurement and Main ResultsSOX17 expression was downregulated in the lungs and pulmonary ECs of IPAH patients. Mice with Tie2Cre mediated Sox17 knockdown and EC-specific Sox17 deletion developed spontaneously mild PH. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced PH in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and anti-apoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP signaling. E2F Transcription Factor 1 (E2F1) signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction and PH development. ConclusionsOur study demonstrated that endothelial SOX17 deficiency induces PH through E2F1 and targeting E2F1 signaling represents a promising approach in PAH patients.

physiology↗

bioRxiv2022

A new LD protein, ApoL6 disrupts the Perilipin 1-HSL interaction to inhibit lipolysis

ApoL6 is a new LD-associated protein containing an apoprotein-like domain, expressed mainly in adipose tissue, specifically in adipocytes. ApoL6 expression is low in fasting but induced upon feeding. ApoL6 knockdown results in smaller LD with lower triglyceride (TAG) content in adipocytes, while ApoL6 overexpression causes larger LD with higher TAG content. We show that ApoL6 effect in adipocytes is by inhibition of lipolysis. While ApoL6, Perilipin 1 (Plin1) and HSL can form a complex on LD, C-terminal domain of ApoL6 directly interacts with Plin1, to compete with Plin1 binding to HSL through Plin1 N-terminal domain, thereby keeping HSL in a "stand by" status. Thus, ApoL6 ablation decreases WAT mass, protecting mice from diet-induced obesity, while adipose overexpression increases WAT mass to bring obesity and insulin resistance with hepatosteatosis, making ApoL6 a potential future target against obesity and diabetes.

molecular biology↗

bioRxiv2022

3D Printed Skull Cap and Benchtop Fabricated Microwire-based Microelectrode Array for Custom Rat Brain Recordings

Microwire microelectrode arrays (MEAs) have been a popular low-cost tool for chronic electrophysiological recordings. Multi-MEA implantations can reveal electrical dynamics crucial to brain function. However, both the fabrication and implantation procedures for multi-MEAs on a single rodent are time-consuming and highly manual skill-dependent for quality. To enable in-house design, fabrication, and implantation of custom microwire MEAs, we developed (1) a computer-aided designed and 3D printed skull cap for pre-determined implantation locations of each MEA and (2) a benchtop fabrication approach for low-cost custom microwire MEAs. A proof-of-concept design of 32-channel 4-MEA (8-wire each) recording system was prototyped and tested through Sprague Dawley rat recordings. The skull cap design based on CT-scan of single rat conforms well with multiple Sprague Dawley rats of various size, age, and weight with minimal bregma alignment error. The prototyped 32-channel system were able to record spiking activities over 5 months. In comparison with conventional stereotactic surgeries, the skull cap system simplifies the implantation location alignment for each MEA by embedding them into the pre-printed designs, thus dramatically reducing the surgical time and effort and increasing the accuracy and repeatability. Compared to commercially available custom microwire MEAs, this in-house fabrication method enables neuroscience labs to create a custom recording apparatus with lower cost and shorter lead time for design modifications. A new methodology for neuroscience labs to fabricate and insert custom microwire MEAs has been developed and it could be easily generalized to enable low-cost highly-custom multi-region recording/stimulation studies. HighlightsO_LI3D printed skull caps as implantation platform for multi-region rat brain recording C_LIO_LIComputer-aided design for custom cap geometry and predetermined implantation location C_LIO_LIBenchtop microwire fabrication approach for in-house custom microelectrode arrays C_LIO_LIDuplicable and generalizable design, fabrication, and implantation methodologies C_LI

neuroscience↗

bioRxiv2022

Disentangled multi-subject and social behavioral representations through a constrained subspace variational autoencoder (CS-VAE)

Effectively modeling and quantifying behavior is essential for our understanding of the brain. Modeling behavior in naturalistic settings in social and multi-subject tasks remains a significant challenge. Modeling the behavior of different subjects performing the same task requires partitioning the behavioral data into features that are common across subjects, and others that are distinct to each subject. Modeling social interactions between multiple individuals in a freely-moving setting requires disentangling effects due to the individual as compared to social investigations. To achieve flexible disentanglement of behavior into interpretable latent variables with individual and across-subject or social components, we build on a semi-supervised approach to partition the behavioral subspace, and propose a novel regularization based on the Cauchy-Schwarz divergence to the model. Our model, known as the constrained subspace variational autoencoder (CS-VAE), successfully models distinct features of the behavioral videos across subjects, as well as continuously varying differences in social behavior. Our approach vastly facilitates the analysis of the resulting latent variables in downstream tasks such as uncovering disentangled behavioral motifs, the efficient decoding of a novel subjects behavior, and provides an understanding of how similarly different animals perform innate behaviors.

neuroscience↗

bioRxiv2022

TMEM100, a Lung-Specific Endothelium Gene

The heterogeneity of endothelium across different organs was recently explored using single-cell RNA-sequencing analysis. Compared to other organs, the lung exhibits a distinct structure composed of a thin layer of capillary for efficient gas exchange. In this study, we demonstrate that Tmem100 is a lung-specific endothelium gene.

physiology↗

bioRxiv2022

Specific Deletion of Axin1 Leads to Activation of β-Catenin/BMP Signaling Resulting in Fibular Hemimelia Phenotype in Mice

Axin1 and Axin2 are key regulators of canonical Wnt signaling pathway. The roles of Axin1 and Axin2 in skeletal development and in disease development have not been fully defined. Here, we reported that Axin1 and Axin2 are essential for lower limb development. Specific deletion of Axin1 in limb mesenchymal cells leads to fibular hemimelia (FH)-like phenotype, associated with tarsal coalition. Further studies demonstrated that FH disease is associated with additional defects resembling to the proximal femoral focal deficiency (PFFD) in Axin1/Axin2 double knockout (KO) mice. We then provided in vivo evidence showing that Axin1 controls limb development through both canonical {beta}-catenin and BMP signaling pathways. We demonstrated that inhibition of {beta}-catenin or BMP signaling could significantly reverse the FH phenotype in mice. Together, our findings revealed that integration of Wnt and BMP signaling by Axin1 is required for lower limb development. Defects in Axin1 and Axin2 signaling could lead to the development of FH disease.

developmental biology↗

bioRxiv2021

Endothelial PHD2 Deficiency Induces Nitrative Stress via Suppression of Caveolin-1 in Pulmonary Arterial Hypertension

Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 [PHD2]) with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP, also known as a peroxynitrite scavenger) treatment inhibited obliterative pulmonary vascular remodeling and attenuated severe PAH in Egln1Tie2Cre mice. Genetic restoration of endothelial Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PAH and improved right heart function. These data suggest that suppression of endothelial Cav1 expression secondary to PHD2 deficiency augments nitrative stress, which contributes to obliterative vascular remodeling and severe PAH. Thus, reactive oxygen/nitrogen species scavenger might have great therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.

physiology↗

bioRxiv2021

Micro-dissection and integration of long and short reads to create a robust catalog of kidney compartment-specific isoforms

Studying isoform expression at the microscopic level has always been a challenging task. A classical example is kidney, where glomerular and tubulo-insterstitial compartments carry out drastically different physiological functions and thus presumably their isoform expression also differs. We aim at developing an experimental and computational pipeline for identifying isoforms at microscopic structure-level. We microdissed glomerular and tubulo-interstitial compartments from healthy human kidney tissues from two cohorts. The two compartments were separately sequenced with the PacBio RS II platform. These transcripts were then validated using transcripts of the same samples by the traditional Illumina RNA-Seq protocol, distinct Illumina RNA-Seq short reads from European Renal cDNA Bank (ERCB) samples, and annotated GENCODE transcript list, thus identifying novel transcripts. We identified 14,739 and 14,259 annotated transcripts, and 17,268 and 13,118 potentially novel transcripts in the glomerular and tubulo-interstitial compartments, respectively. Of note, relying solely on either short or long reads would have resulted in many erroneous identifications. We identified distinct pathways involved in glomerular and tubulointerstitial compartments at the isoform level.We demonstrated the possibility of micro-dissecting a tissue, incorporating both long- and short-read sequencing to identify isoforms for each compartment.

bioinformatics↗

bioRxiv2021

Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

BackgroundCardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. Methods and ResultsMice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) (Egln1Tie2Cre) exhibited left ventricular (LV) hypertrophy evident by increased thickness of anterior and posterior wall and LV mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced LV hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2 as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2 attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. ConclusionsThe present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2 dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2 signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

physiology↗

bioRxiv2020

Ultra-fast Prediction of Somatic Structural Variations by Reduced Read Mapping via Pan-Genome k-mer Sets

Genome rearrangements often result in copy number alterations of cancer-related genes and cause the formation of cancer-related fusion genes. Current structural variation (SV) callers, however, still produce massive numbers of false positives (FPs) and require high computational costs. Here, we introduce an ultra-fast and high-performing somatic SV detector, called ETCHING, that significantly reduces the mapping cost by filtering reads matched to pan-genome and normal k-mer sets. To reduce the number of FPs, ETCHING takes advantage of a Random Forest classifier that utilizes six breakend-related features. We systematically benchmarked ETCHING with other SV callers on reference SV materials, validated SV biomarkers, tumor and matched-normal whole genomes, and tumor-only targeted sequencing datasets. For all datasets, our SV caller was much faster ([≥]15X) than other tools without compromising performance or memory use. Our approach would provide not only the fastest method for largescale genome projects but also an accurate clinically practical means for real-time precision medicine.

bioinformatics↗

bioRxiv2020

Integrated characterization of SARS-CoV-2 genome, microbiome, antibiotic resistance and host response from single throat swabs

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, poses a severe threat to humanity. Rapid and comprehensive analysis of both pathogen and host sequencing data is critical to track infection and inform therapies. In this study, we performed unbiased metatranscriptomic analysis of clinical samples from COVID-19 patients using a newly-developed RNA-seq library construction method (TRACE-seq), which utilizes tagmentation activity of Tn5 on RNA/DNA hybrids. This approach avoids the laborious and time-consuming steps in traditional RNA-seq procedure, and hence is fast, sensitive and convenient. We demonstrated that TRACE-seq allowed integrated characterization of full genome information of SARS-CoV-2, putative pathogens causing coinfection, antibiotic resistance and host response from single throat swabs. We believe that the integrated information will deepen our understanding of pathogenesis and improve diagnostic accuracy for infectious diseases.

microbiology↗

bioRxiv2020

Dot1L interacts with Zc3h10 to activate UCP1 transcription and promote thermogenesis

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1L, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the UCP1 promoter and other BAT genes. Through a direct interaction, Dot1L is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1L is induced during brown fat cell differentiation and by cold exposure and that Dot1L and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1L ablation in mice using UCP1-Cre prevents activation of UCP1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1L plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

developmental biology↗