Biology subjects

Svaren, J.

Publications and source records attributed to Svaren, J..

7 recordsLinked to original sources

bioRxiv2025

Integration of Nuclear Receptors into a Schwann cell Gene Regulatory Network

Peripheral nerve function depends on the proper formation and maintenance of Schwann cells. During development, large diameter axons are enveloped by single, myelinating Schwann cells whereas clusters of small diameter axons are surrounded by nonmyelinating Schwann cells in Remak bundles. The transcription factor SRY-box 10 (SOX10) is required for the development of Schwann cells, but its functions in different neural crest and glial lineages have shown that SOX10 commonly cooperates with other transcription factors to activate cell-specific gene programs. In a previous study, we compared SOX10-bound regulatory elements in Schwann cells and identified a specific enrichment for nuclear receptor motifs at SOX10 binding sites in Schwann cells. NR2F1 and NR2F2 (Coup-TFI/Coup-TFII) are expressed from neural crest through Schwann cell maturity, and knockdown of nuclear receptors Nr2f1 and Nr2f2 in primary Schwann cells downregulated several myelin genes. In this study, we have identified a NR2F-regulated target gene network in Schwann cells, which revealed enrichment for nonmyelinating Schwann cell genes. Cut&Run assays in S16 Schwann cells revealed novel, genome-wide binding sites of NR2F2 and two downstream transcription factors: 1) Retinoid X Receptor Gamma (RXRG), which is also expressed preferentially in nonmyelinating Schwann cells, and 2) TEA-Domain factor (TEAD1), which is an important HIPPO pathway component required for Remak bundle formation. Our study elucidates the transcriptional cooperation that programs the regulatory network in nonmyelinating Schwann cells.

neuroscience↗

bioRxiv2024

Single-cell multi-omics analysis reveals cooperative transcription factors for gene regulation in oligodendrocytes

Oligodendrocytes are the myelinating cells within the central nervous system. Many oligodendrocyte genes have been associated with brain disorders. However, how transcription factors (TFs) cooperate for gene regulation in oligodendrocytes remains largely uncharacterized. To address this, we integrated scRNA-seq and scATAC-seq data to identify the cooperative TFs that co-regulate the target gene (TG) expression in oligodendrocytes. First, we identified co- binding TF pairs whose binding sites overlapped in oligodendrocyte-specific regulatory regions. Second, we trained a deep learning model to predict the expression level of each TG using the expression levels of co-binding TFs. Third, using the trained models, we computed the TF importance and TF-TF interaction scores for predicting TG expression by the Shapley interaction scores. We found that the co-binding TF pairs involving known important TF pairs for oligodendrocyte differentiation, such as SOX10-TCF12, SOX10-MYRF, and SOX10-OLIG2, exhibited significantly higher Shapley scores than others (t-test, p-value < 1e-4). Furthermore, we identified 153 oligodendrocyte-associated eQTLs that reside in oligodendrocyte-specific enhancers or promoters where their eGenes (TGs) are regulated by cooperative TFs, suggesting potential novel regulatory roles from genetic variants. We also experimentally validated some identified TF pairs such as SOX10-OLIG2 and SOX10-NKX2.2 by co-enrichment analysis, using ChIP-seq data from rat peripheral nerve.

bioinformatics↗

bioRxiv2024

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1 is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.

neuroscience↗

bioRxiv2023

NetREm: Network Regression Embeddings reveal cell-type transcription factor coordination for gene regulation

Transcription factor (TF) coordination plays a key role in target gene (TG) regulation via protein-protein interactions (PPIs) and DNA co-binding to regulatory elements. Single-cell technologies facilitate gene expression measurement for individual cells and cell-type identification, yet the connection between TF coordination and TG regulation of various cell types remains unclear. To address this, we have developed a novel computational approach, Network Regression Embeddings (NetREm), to reveal cell-type TF-TF coordination activities for TG regulation. NetREm leverages network-constrained regularization using prior knowledge of direct and/or indirect PPIs among TFs to analyze single-cell gene expression data. We test NetREm by simulation data and benchmark its performance in 4 real-world applications that have gold standard TF-TG networks available: mouse (mESCs) and simulated human (hESCs) embryonic stem (ESCs), human hematopoietic stem (HSCs), and mouse dendritic (mDCs) cells. Further, we showcase NetREms ability to prioritize valid novel TF-TF coordination links in human Peripheral Blood Mononuclear cell (PBMC) sub-types. We apply NetREm to analyze various cell types in both central (CNS) and peripheral (PNS) nerve system (NS) (e.g. neuronal, glial, Schwann cells (SCs)) as well as in Alzheimers disease (AD). Our findings uncover cell-type coordinating TFs and identify new TF-TG candidate links. We validate our top predictions using Cut&Run and knockout loss-of-function expression data in rat/mouse models and compare results with additional functional genomic data, including expression quantitative trait loci (eQTL) and Genome-Wide Association Studies (GWAS) to link genetic variants (single nucleotide polymorphisms (SNPs)) to TF coordination. NetREm is open-source available on GitHub as a software package.

bioinformatics↗

bioRxiv2022

JUN Regulation of Injury-induced Enhancers in Schwann Cells

Schwann cells play a critical role after peripheral nerve injury by clearing myelin debris, forming axon-guiding Bands of Bungner, and re-myelinating regenerating axons. Schwann cells undergo epigenomic remodeling to differentiate into a repair state that expresses unique genes, some of which are not expressed at other stages of Schwann cell development. We previously identified a set of enhancers that are activated in Schwann cells after nerve injury, and we determined if these enhancers are pre-programmed into the Schwann cell epigenome as poised enhancers prior to injury. Poised enhancers share many attributes of active enhancers, such as open chromatin, but are marked by repressive H3K27 trimethylation (H3K27me3) rather than H3K27ac. We find that most injury-induced enhancers are not marked as poised enhancers prior to injury indicating that injury-induced enhancers are not pre-programmed in the Schwann cell epigenome. Injury-induced enhancers are enriched with AP-1 binding motifs, and the c-JUN subunit of AP-1 had been shown to be critical to drive the transcriptional response of Schwann cells after injury. Using in vivo ChIP-seq analysis we find that c-JUN binds to a subset of injury-induced enhancers. To test the role of specific injury-induced enhancers, we focused on c-JUN-binding enhancers upstream of the Sonic Hedgehog (Shh) gene, which is only upregulated in repair Schwann cells compared to other stages of Schwann cell development. We confirm that c-JUN regulates these enhancers and also show that the enhancers are required for robust induction of the Shh gene after injury. Significance StatementThe pro-regenerative actions of Schwann cells after nerve injury depends on upon profound reprogramming of the epigenome. The repair state is directed by injury-induced transcription factors, like JUN, which is uniquely required after nerve injury. In this study, we test whether the injury program is pre-programmed into the epigenome as poised enhancers and define which enhancers bind JUN. Finally, we test the roles of these enhancers by performing CRISPR-mediated deletion of JUN-bound injury enhancers in the Sonic hedgehog gene. While many long range enhancers drive expression of Sonic hedgehog at different developmental stages of specific tissues, these studies identify an entirely new set of enhancers that are required for Sonic hedgehog induction in Schwann cells after injury.

neuroscience↗

bioRxiv2020

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.

neuroscience↗

bioRxiv2018

Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.\n\n\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@103281aorg.highwire.dtl.DTLVardef@3dc68eorg.highwire.dtl.DTLVardef@1b6c5feorg.highwire.dtl.DTLVardef@80e419org.highwire.dtl.DTLVardef@1ff2591_HPS_FORMAT_FIGEXP M_TBL C_TBL

neuroscience↗