Biology subjects

Yalamanchili, H. K.

Publications and source records attributed to Yalamanchili, H. K..

11 recordsLinked to original sources

bioRxiv2026

Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates α-Synuclein pathology in a Parkinson's disease mouse model

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinsons disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of -synuclein (-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and -Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF- and IL-1 stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1--Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and -Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal -Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1--Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129--Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to -Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/726454v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@150a3e3org.highwire.dtl.DTLVardef@137b5caorg.highwire.dtl.DTLVardef@7fe373org.highwire.dtl.DTLVardef@2d996e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Lineage Tracing Reveals a Shared Cellular Origin for Supraclavicular Brown and Inguinal Beige Adipocytes

The metabolic importance of brown adipose tissue (BAT) has been recognized, but the origins of BAT, particularly supraclavicular BAT (scBAT), are less clear. Here, we traced the origin of scBAT to Mef2c-anterior heart field (AHF)-marked cells. Mef2c-AHF-marked cells isolated from scBAT can spontaneously differentiate into brown adipocytes, express mesenchymal stem cell markers, and can be isolated from the stromal-vascular fraction (SVF) of wild-type scBAT as [CD31-CD45-SCA-1+CD29+CD34-CD24-] (CD34-) cells. Mef2c-AHF-marked cells substantially overlap with Prrx1-marked cells in scBAT, which also contribute to beige adipocytes in inguinal white adipose tissue (iWAT) during development. Similarly, CD34- cells isolated from the SVF of iWAT can spontaneously differentiate into beige adipocytes in vitro. Using intersectional tracing, we revealed that common progenitors of Mef2c-AHF- and Prrx1-marked cells in scBAT emerge from the developing heart. Thus, these studies reveal a common origin for scBAT and cardiac tissue and a close lineage relationship between scBAT and beige adipocytes of the iWAT.

developmental biology↗

bioRxiv2025

Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16INK4a, p21CIP1, senescence-associated {beta}-galactosidase (SA{beta}gal), {gamma}H2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as "senosensitizers"), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.

cell biology↗

bioRxiv2024

The big tau splice isoform resists Alzheimer's-related pathological changes

In Alzheimers disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus1-3. However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed "big tau" is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.

neuroscience↗

bioRxiv2023

Differential effects of MATR3 variants on its cryptic splicing repression function

MATR3 is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.

molecular biology↗

bioRxiv2023

The epigenetic response of mouse brown adipose tissue to cold stress: histone proteoform, DNA methylation, and RNA expression

Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top- down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8{degrees}C), mild cold/room temperature (RT, 22{degrees}C), or severe cold (SC, 8{degrees}C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression data suggest a role for epigenetic modification of DNA in gene regulation in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. Taken together, our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.

systems biology↗

bioRxiv2023

PolyAMiner-Bulk: A Machine Learning Based Bioinformatics Algorithm to Infer and Decode Alternative Polyadenylation Dynamics from bulk RNA-seq data

More than half of human genes exercise alternative polyadenylation (APA) and generate mRNA transcripts with varying 3 untranslated regions (UTR). However, current computational approaches for identifying cleavage and polyadenylation sites (C/PASs) and quantifying 3UTR length changes from bulk RNA-seq data fail to unravel tissue- and disease-specific APA dynamics. Here, we developed a next-generation bioinformatics algorithm and application, PolyAMiner-Bulk, that utilizes an attention-based machine learning architecture and an improved vector projection-based engine to infer differential APA dynamics accurately. When applied to earlier studies, PolyAMiner-Bulk accurately identified more than twice the number of APA changes in an RBM17 knockdown bulk RNA-seq dataset compared to current generation tools. Moreover, on a separate dataset, PolyAMiner-Bulk revealed novel APA dynamics and pathways in scleroderma pathology and identified differential APA in a gene that was identified as being involved in scleroderma pathogenesis in an independent study. Lastly, we used PolyAMiner-Bulk to analyze the RNA-seq data of post-mortem prefrontal cortexes from the ROSMAP data consortium and unraveled novel APA dynamics in Alzheimers Disease. Our method, PolyAMiner-Bulk, creates a paradigm for future alternative polyadenylation analysis from bulk RNA-seq data.

bioinformatics↗

bioRxiv2021

MECP2pedia: A Comprehensive Transcriptome Portal for MECP2 Disease Research

Mutations in MeCP2 result in a crippling neurological disease, but we lack a lucid picture of MeCP2s molecular role. Focusing on individual transcriptomic studies yields inconsistent differentially expressed genes. We have aggregated and homogeneously processed modern public MeCP2 transcriptome data, which we present in a web portal. With this big data, we discovered a commonly perturbed core set of genes that transcends the limitations of any individual study. We then found distinct consistently up and downregulated subsets within these genes. We observe enrichment for this mouse core in other species MeCP2 models and see overlap between this core and ASD models. Analysis of signal to noise finds that many studies lack enough biological replicates. By integrating and examining transcriptomic data at scale, we have generated a valuable resource and insight on MeCP2 function.

bioinformatics↗

bioRxiv2020

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

BackgroundTau neurofibrillary tangle pathology characterizes Alzheimers disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. MethodsPaired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutation causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. ResultsTauWT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. ConclusionsOur results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

genomics↗

bioRxiv2019

Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease

In Alzheimers disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal core components. In Drosophila models, pan-neuronal Tau expression triggers reductions in core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss-of-function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA-sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.

neuroscience↗

bioRxiv2017

Bias toward long gene misregulation in synaptic disorders can be an artefact of amplification-based methods

Several recent studies have suggested that genes that are longer than 100 kilobases are more likely to be misregulated in neurological diseases associated with synaptic dysfunction, such as autism and Rett syndrome. These length-dependent transcriptional changes are modest in Mecp2-mutant samples, but, given the low sensitivity of high-throughput transcriptome profiling technology, the statistical significance of these results needs to be re-evaluated. Here, we show that the apparent length-dependent trends previously observed in MeCP2 microarray and RNA-Sequencing datasets, particularly in genes with low fold-changes, disappeared after accounting for baseline variability estimated from randomized control samples. As we found no similar bias with NanoString technology, this long-gene bias seems to be particular to PCR amplification-based platforms. In contrast, authentic long gene effects, such as those caused by topoisomerase inhibition, can be detected even after adjustment for baseline variability. Accurate detection of length-dependent trends requires establishing a baseline from randomized control samples.\n\nHIGHLIGHTSO_LILength-dependent gene misregulation is not intrinsic to Mecp2 disruption.\nC_LIO_LITopoisomerase inhibition produces an authentic long gene bias.\nC_LIO_LIPCR amplification-based high-throughput datasets are biased toward long genes.\nC_LI

neuroscience↗