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Biology subjects

Das, M.

Publications and source records attributed to Das, M..

At least 19 recordsLinked to original sources

Shear Strain Stiffening in Cartilage is Governed by a Mechanical Phase Transition

Large shear deformation in cartilage can lead to tissue failure and injury, which are often precursors to diseases such as post-traumatic osteoarthritis. Under shear, cartilage strain-stiffens prior to failure, which makes stiffening an important indicator of changes to the loading of the extracellular matrix that gives rise to this tissue's properties. While a variety of stiffening mechanisms ranging from uncrimping to fiber-alignment have been explored, whether such mechanisms apply to the depth dependent shear strain stiffening in articular cartilage remains poorly understood. Here, we present experiments and theory that support the idea that the strain-stiffening behavior is caused by a mechanical phase transition from a random isotropic network whose mechanics arise primarily from bending-dominated modes to one where the mechanics arise from stretching-dominated modes. Indeed, consistent with network model predictions, we find that stress-strain data for all depths can be collapsed onto a single universal curve that diverges at a depth-dependent critical strain. These results show that increasing the local concentration of collagen, which constitutes the primary load-bearing network in cartilage, decreases the critical strain at which the strain-stiffening transition occurs, while increasing the low-strain elastic modulus. Furthermore, we demonstrate that bulk compression leads to a higher critical strain and decreased low-strain elastic modulus. Network simulations capture this rich behavior, and indicate that under compression the network collapses, which allows for larger strains before the transition from bending-dominated to stretching-dominated mechanics occurs. Collectively, these findings shed light on the roles that tissue composition and axial strain play in the mechanisms that organize how articular cartilage stiffens during the lead-up to injury.

biophysics↗

Variation in multiple classes of simple sequence repeats can alter drug susceptibility in Mycobacterium tuberculosis

Insertions and deletions (INDELs) in simple sequence repeats (SSRs) generate relatively high-frequency reversible genetic changes that facilitate bacterial adaptation to changing environments. Analyses of global Mycobacterium tuberculosis (Mtb) isolates indicate that many SSRs are under diversifying selection, and several of the resulting INDELs in homopolymer tracts (HTs) can increase the pathogen's fitness during exposure to host and antibiotic stresses. However, the functional impact of most variable SSRs, particularly those within more complex repeat sequences than HT, remains unclear. Here, we combine phylogenomic analysis of clinical Mtb strains from Vietnam and Peru with in vitro experimental validation of engineered strains to identify SSR INDELs that alter antibiotic susceptibility. Our findings demonstrate that INDELs across multiple SSRs of differing repeat composition are highly variable and correlate with clinical antibiotic resistance. These variants included frameshifting HT INDELs in ppe13, glpK, Rv2081c, and ppsA, and in-frame trinucleotide (triplet) SSR INDELS in ponA1, ppe53, and ppe59 that produce much more subtle changes in protein structure. Reconstruction of these INDELs in an isogenic background identified four variants that directly reduce drug potency, including a triplet SSR deletion in ppe53 that conferred intermediate resistance to isoniazid, rifampicin, and streptomycin. The clinically prevalent ppe53 CGCdel mutation shortens a polyalanine stretch adjacent to the conserved WxG domain and impairs the processing and secretion of the full-length protein. Overall, our work provides additional evidence of selective pressure across Mtb SSRs and demonstrates the significance of in-frame INDELs within triplet SSRs, highlighting their contribution to the evolution of antibiotic resistance.

microbiology↗

HANSEN: An Integrated Structural and Functional Proteome Resource for Structure-Guided Drug Discovery in Mycobacterium leprae

Leprosy remains a leading infectious cause of preventable disability, yet its causative agent, Mycobacterium leprae (M. leprae), is structurally under-characterised. Only ten Protein Data Bank (PDB) entries represent seven of its 1,603 protein-coding genes. We present HANSEN, a proteome-wide structural and functional resource for M. leprae. Monomeric and oligomeric models were generated with AlphaFold 3, Boltz-1, Boltz-2 and Chai-1, and annotated with per-residue confidence, predicted aligned error and, for assemblies, interface confidence. Ligand-binding pockets were predicted with AF2BIND, P2Rank and fpocket, template-derived ligands were modelled within oligomeric complexes, residue-level B-cell epitope propensity was estimated with DiscoTope-3.0, and gene essentiality was transferred from Mycobacterium tuberculosis transposon-sequencing labels. These features are integrated in a relational database with interactive visualisation and combined into a calibrated Target Priority Score that ranks all 1,603 proteins into four tiers and recovers established antimycobacterial targets. HANSEN (https://hansen-leprosy.medschl.cam.ac.uk/home) provides a practical basis for target prioritisation and structure-guided drug discovery in leprosy.

bioinformatics↗

Pharmacologic eIF2B Activation Rescues Neuropathy in CMT2 Subtypes by Normalizing the Integrated Stress Response

Among the many subtypes of Charcot-Marie-Tooth (CMT) disease, several result from mutations in genes encoding aminoacyl-tRNA synthetases, enzymes required for tRNA charging during cytoplasmic and mitochondrial translation. We report that activation of the integrated stress response (ISR) pathway is a shared molecular feature of tRNA synthetase-associated and other axonal CMT subtypes. RTX-117, a CNS-penetrant small molecule currently in Phase 1 clinical trials, targets eukaryotic initiation factor 2B (eIF2B), a key modulator of protein synthesis and the ISR pathway. Using cryo-EM studies, we have characterized the binding mode of RTX-117 to the eIF2B decamer. In GarsP278KY/+ mice, which develop early onset motor defects and axonal pathology that recapitulate CMT2D symptoms from tRNA synthetase mutations, RTX-117 treatment started after disease onset reduced chronic ISR activation and produced significant functional and electrophysiological improvement. We further identify ISR targets, including secreted proteins such as GDF15 and FGF21 that may serve as translational biomarkers for treatment response to RTX-117 in CMT disease. Broader surveillance of the ISR pathway across models of neurodegeneration reveals strong activation in several diseases and a correlation with disease progression, particularly in models of Alzheimers disease. These findings identify chronic ISR activation as a recurrent, though not universal, pathological mechanism of neurodegenerative disease models. Overall, our study identifies candidate biomarkers for CMT disease subtypes associated with defects in translational homeostasis and supports eIF2[a]-ATF4 axis modulation as a promising therapeutic strategy for this disease class. One Sentence SummaryRTX-117, a clinical stage eIF2B activator, blunts chronic ISR activation and improves nerve and motor function in a mouse model of Charcot-Marie-Tooth Disease Type 2D.

cell biology↗

Stress-Induced Mechanical Memory in Respiratory Mucus: Anisotropy, Network Reorganization, and Directional Transport

Mucus transport is essential for lung health, as ciliated cells constantly propel mucus outward to clear bacteria, viruses, and particles. This defense relies on a material that must be elastic enough to maintain ciliary traction, but capable of reorganizing under sustained directional loading. How the mucin network reconciles these demands, and whether it retains a memory of the stresses it experiences, remains poorly understood. Here we show that lung mucus develops a persistent, direction-dependent mechanical asymmetry under physiologically relevant stress--a mechanical memory encoded in the slow scaffold of the network. Using bulk rheology, we find that directional pre-stress produces a residual anisotropy that grows with stress magnitude and persists long after the load is removed. A transient network model attributes this memory to a separation of timescales between transient bonds and a long-lived crosslink scaffold, and particle-tracking microrheology confirms that the memory reorganizes the network geometry at the scale of biological particles, biasing tracer diffusion along the axis of applied stress. The stresses required to induce memory are within the range generated by ciliary beating and remain below the mucus yield threshold, suggesting that mucociliary clearance operates in a regime where directional alignment accumulates without compromising the coherence of the mucus layer. This proximity to yield may not be coincidental, it allows mucus to accumulate mechanical memory under physiological forcing while remaining poised to flow during clearance events such as coughing.

biophysics↗

HEALTHY AGING AS INFORMATION DIVERGENCE IN THE MULTIPLEX BRAIN

AO_SCPLOWBSTRACTC_SCPLOWUnderstanding the co-evolution of the human brains structural scaffold and functional traffic across the adult lifespan remains a fundamental challenge in neuroscience. While age-related degradation in grey matter and functional activation is well-documented, the joint trajectory of the structural (SC) and functional (FC) connectomes is often overlooked due to the lack of an integrative framework. Here, we model the brain as a multiplex network to quantify the information-theoretic interdependencies between these two layers in a cross-sectional cohort of 589 healthy individuals (ages 18-88) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset. Using Jensen-Shannon Divergence and relative entropy metrics, we identify a fundamental organizing principle of healthy aging characterized by: a progressive information divergence where functional dynamics increasingly "untether" from their underlying structural constraints. Our results reveal that this decoupling follows a robust linear trajectory, yet is highly spatially hetero-geneous. Meso-scale community analysis using the Multiplex Map Equation identifies subcortical hubs--specifically the putamen, pallidum, caudate, and thalamus--as the primary epicenters of age-related SC-FC divergence. This topological shift toward functional independence in subcortical "switchboards" provides a mechanistic connectomic signature for the well-documented decline in fluid intelligence and motor adaptation that accompanies aging. In striking contrast, the limbic core (hippocampus and entorhinal cortex) exhibits remarkable stability across the lifespan, suggesting a biological imperative to preserve high-fidelity memory circuits amidst global communicative rewiring. By framing healthy aging as a systematic subcortical untethering alongside limbic resilience, our work provides a powerful new multiplex baseline to distinguish normative cognitive decline from the early topological signals of neurodegenerative disease. Significance StatementHealthy aging involves a fundamental reorganization of the brains information architecture. By modeling the brain as a multiplex network and leveraging information-theoretic measures, we demonstrate that adult lifespan development is characterized by a progressive "untethering" of functional dynamics from their underlying structural constraints. This decoupling is driven by a striking geometric paradox within subcortical hubs: while physical structural scaffolds undergo severe network constriction and isolation, their functional boundaries expand and blur in a state of neural de-differentiation. This architectural mismatch is mediated by a synchronized prefrontal-to-limbic pathway shift that operates collinearly with chronological age and mirrors the selective decline of fluid intelligence and motor adaptation that accompanies aging. Our work establishes a rigorous multiplex framework that moves beyond descriptive accounts of neural tissue loss to provide a normative baseline for distinguishing healthy brain aging from neurodegeneration.

neuroscience↗

Combinatorial constraints predict that mitochondrial networks contain a large component

Mitochondria often form branching membrane networks distributed throughout the cell interior. In many, but not all, cell types, these networks are observed to consist of one large connected component together with many smaller fragments. Why does this pattern arise? Does it reflect a specific biological function, an external biophysical constraint, or something simpler? Using results from extremal graph theory, we prove a new theorem which suggests that, under a sufficiently broad sampling of the space of mitochondria-like graphs, the predominance of three-way junctions makes the appearance of a large component likely. This suggests that, in some settings, a large component may serve as a useful null model for mitochondrial network structure rather than requiring a dedicated explanation. More broadly, our result points towards testable predictions, since systematic deviations from this baseline may help reveal additional constraints or mechanisms shaping mitochondrial morphology.

systems biology↗

Emergent Morphologies, Slow Dynamics, and Phase Behavior in Dps:DNA assemblies

The DNA-binding protein from starved cells (Dps) compacts bacterial DNA into stress-protective condensates, but the physical ingredients that are sufficient to produce the observed morphological and dynamical phenomenology remain unclear. Here we use Dps:DNA as the motivation for a broader soft-matter question: which properties govern the co-condensation of a semiflexible polymer with a binding co-solute, and how is the resulting condensate morphology selected? We combine coarse-grained Brownian dynamics (BD) simulations, in which DNA is a semiflexible bead-spring chain and Dps a spherical particle interacting through heterotypic attraction and homotypic repulsion, with a ternary Flory-Huggins free energy evolved under conserved Cahn-Hilliard-Cook dynamics. Both frameworks show that the condensate morphology is governed jointly by the heterotypic Dps:DNA attraction and by composition: attraction drives co-condensation, while at fixed attraction the relative abundance of the two species selects between extended, network-like structures and compact, droplet-like condensates. That two independent models, sampling different concentration regimes, both show composition-controlled morphology selection indicates it is a robust feature of the co-condensation thermodynamics. The simulations further reveal slow, heterogeneous dynamics: sub-diffusive Dps motion and a stretched-exponential collapse of chain dimensions, signatures of the dynamical arrest that accompanies compaction. The framework provides general, transferable principles for protein-nucleic-acid phase separation in soft and living matter.

biophysics↗

Quantifying the impact of genetic mutations on enhancer dynamics

Transcriptional regulation is mediated by enhancers, yet how genetic perturbations alter enhancer activity and gene expression remains poorly understood. We developed UDI-UMI-STARR-seq, which integrates dual indexes and unique molecular identifiers, and combined it with RNA-seq to profile the effects of perturbations on enhancer activity and target gene expression. We applied this approach to a library of 253,632 fragments representing 46,142 cell type-specific candidate enhancers and assessed the impact of CRISPR/Cas9-mediated deletion of six transcription factors (or TFs; ATF2, CTCF, FOXA1, LEF1, TCF7L2, and SCRT1) with diverse regulatory roles. Across knockout lines, we identified responsive enhancers that were either repressed or induced, often through motifs such as the p53 family of TFs. Enhancer-gene mapping revealed TF-specific programs, including repression of Wnt/p53 targets with ATF2 or LEF1 loss, downregulation of the FIRRE locus with CTCF loss, and compensatory upregulation of RNA polymerase II regulators following FOXA1 depletion. A deep learning model trained on enhancer sequences recapitulated core principles of enhancer grammar, including cooperative motif syntax and the influence of flanking sequence context. Applying this framework to the neurodevelopmental disorder-associated 16p12.1 deletion identified responsive enhancers linked to genes involved in axon guidance, synaptic plasticity, and translational control, providing a scalable readout of enhancer dynamics generalizable to genetic mutations.

genomics↗

RB1 gene mutations and their association with Endometrial Cancer

Retinoblastoma gene (RB1) mutation has been reported in lung cancer, retinoblastoma and cervical cancer etc. Here, we elucidate the involvement of RB1 mutations and their regulation in endometrial cancer. Analysis of mutation data of 547 endometrial cancer samples revealed that 12% of samples harboured RB1 mutations. However, 26% of the patients aged between 30 and 50 years harboured RB1 mutations, compared to only 10% in the older age group. Further, in silico interaction studies and structural analysis of these novel RB1 mutations and E2F revealed possible physiological relevance. We found 14,117 genes were significantly mutated, and 5,770 genes were differentially expressed in RB1-altered patients. Pathway analysis showed a significant correlation between RB1 mutations and estrogen receptor mutations. Different cancer-related pathways were also altered in RB1-mutated conditions. More importantly, a positive link between RB1 mutations and HPV infection pathways was observed, indicating HPV infections might induce RB1 mutations in endometrial cancer, which could be prevented by early vaccination. Our findings suggest RB1 mutations as a potential contributor to endometrial cancer in younger women, highlighting the importance of viral co-factors in risk assessments, advocating HPV vaccination in individuals with RB1 mutations.

cancer biology↗

BRD2 bridges TFIID and histone acetylation to promote transcriptional initiation

Members of the bromodomain and extraterminal domain (BET) protein family play a central role in transcription by RNA Polymerase II (Pol II). Small-molecule inhibitors that block interaction between BET bromodomains and acetylated histones have been developed to achieve therapeutic benefit. However, the BET protein BRD4 does not require bromodomains to perform its major transcriptional elongation function, and the mechanisms by which other BET proteins regulate transcription remain incompletely understood. Addressing the disparity between pan-BET degraders and BRD4-specific depletion, we report that the BET protein BRD2 generally functions to promote transcriptional initiation in a bromodomain-dependent manner at both promoters and enhancers in human cells. We demonstrate that BRD2 bromodomains preferentially bind to tetra-acetylated histones harboring MOF-mediated H4K16ac, while the BRD2 C terminal domain facilitates recruitment of TFIID. Our studies provide mechanistic insight into the distinct roles of BRD2 in transcriptional initiation through the recruitment of TFIID and BRD4 in transcriptional elongation through the recruitment of CDK9 and controlling proper regulation of gene expression.

biochemistry↗

NASP functions in the cytoplasm to prevent histone H3 aggregation during early embryogenesis

From their molecular birth until their incorporation into chromatin, histones are bound by specific chaperones that serve unique functions in histone trafficking, stability and chromatin deposition. The H3-specific chaperone NASP binds directly to H3 and is required to prevent degradation of soluble H3 in vivo. Where NASP functions and how NASP affects H3 dynamics and stability is unknown. Using the Drosophila early embryo as a model system to understand NASP function in vivo, we show that NASP does not directly affect H3 nuclear import or export rates. Rather, reduced H3 levels in NASP-deficient embryos indirectly affect nuclear import and the amount of H3 deposited into chromatin. Crucially, we find that cytoplasmic NASP prevents H3 aggregation in vivo and that H3 aggregation and degradation are developmentally separable events. Thus, we propose the main function of NASP in vivo is to prevent H3 aggregation, thereby indirectly protecting H3 from degradation.

molecular biology↗

Role of the Arp2/3 Complex in Regulating Mitotic Entry and Progression in S. pombe

Fission yeast undergoes closed mitosis, wherein chromosome segregation occurs inside an intact nucleus. The microtubule organizing center, Spindle Pole Body (SPB) is duplicated in the G2 phase followed by insertion into a fenestra on the nuclear envelope (NE). The SPB then nucleates spindle microtubules at mitotic onset. Here we show that the branched actin network promotes mitotic entry by enabling NE fenestration. Inhibiting the branched actin nucleator Arp2/3 complex with the drug CK666 fail mitotic entry and the few cells that enter mitosis show significant delays. Upon CK666 inhibition, most proteins are correctly recruited to the SPB at the onset of mitosis however they fail to properly recruit the POLO-like kinase Plo1 and the SPB docking protein Cut11, suggesting a failure in SPB insertion. The start of NE fenestration is marked by the formation of a Sad1 ring, a SUN domain protein followed by a Cut11 ring. Super-resolution structured illumination microscopy indicates that CK666-treated cells show impaired Sad1 or Cut11 rings. Furthermore, these cells do not leak NLS-GFP, a hallmark of fenestration failure. In agreement with the role for branched actin in NE fenestration, CK666 treatment after SPB insertion does not show any mitotic entry defects as observed with preprophase-arrested tubulin mutants. We observed a component of the Arp2/3 complex Arc5, and actin-binding proteins Fimbrin and Coronin, on the nuclear envelope within minutes of mitotic onset. In CK666-treated cells where mitosis is delayed, in the absence of branched actin the SPB aberrantly interacts with the actomyosin ring, preventing its proper dynamics. This results in phenotypes such as the formation of multinucleate structures, asymmetric nuclear division, floppy nuclear membrane, and severe bending of spindle microtubules. Our findings demonstrate a novel role for Arp2/3 complex-dependent branched actin in promoting NE fenestration and SPB insertion during mitosis.

cell biology↗

Genome sequencing, de novo assembly and annotation of the commercially important bamboo, Bambusa tulda Roxb.

Bambusa tulda Roxb., a member of the Bambusoideae subfamily, is an ecologically and commercially important plant resource widely distributed on the Indian subcontinent. Our study reports long-read PacBio HiFi sequencing and genome assembly of B. tulda. Flow cytometry analysis revealed its estimated genome size [~]3 Gb. The de novo genome assembly of B. tulda predicted 43 contigs, distributed across three subgenomes, with a total size of 1.37 Gb, contig N50 of 35.69 Mb, and BUSCO score 99%. Repetitive elements constitute 63.31% of the genome. Functional annotation predicted 56,890 protein-coding genes, constituting 19.44% of the genome. This high-quality draft genome assembly will serve as an invaluable resource for future studies on the life history traits, phylogenomic analysis, comparative genomics, and targeted genome modification for important trait improvement of B. tulda.

genomics↗

Comparative evaluation on the fermentative potential of single and assorted fruit and vegetable waste for production of bioethanol

Fruit and vegetable waste (FVW) constitute a large part of municipal solid waste (MSW) and create significant environmental challenges by emitting the greenhouse gas methane. In contrast, these are a big source of fermentable sugar to produce bioenergy. Therefore, in this study, the Scanning Electron Microscopy (SEM), Attenuated total reflectance-fourier-transform infrared spectroscopy (ATR-FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and biochemical quantification of -cellulose and acid-insoluble lignin contents were carried out to compare fermentative potential between single (potato peel vs. orange peel) and assorted vegetable and fruit wastes. Collectively, the study indicates that assorted vegetable waste holds enormous biofuel potential by having low moisture content (6.78 %), moderately low decomposition temperature (Tmax: 299.36 {degrees}C), low crystallinity index (CrI: 19.12%), and high -cellulose contents (32.35 - 47.73 gm%) yielding high sugar (325.65 mg/g). The study also optimized several key fermentation parameters such as pH, sugar concentration and the time to produce bioethanol. It was observed that maximum production of ethanol (2.14%) was achieved at 28{degrees}C, at pH 6.3 with a higher initial sugar concentration of 200mg/g by using Saccharomyces cerevisiae strain NCIM 3594. This study supports the likely utility of unsorted vegetable waste to obtain bioethanol at a mass scale.

plant biology↗

Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans

Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPRmt) activators in C. elegans, we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes a dually localized methionine tRNA synthetase (MetRS). Here, we characterize the UPRmt induction by Y105E8A.20, which we call mars-2, and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show impaired mars-2 activity in the mitochondria triggers UPRmt. This strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.

genetics↗

Modelling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype

Drug resistance and distant metastases are major contributors to mortality in colorectal cancer (CRC). Here we investigate mechanisms underlying acquired resistance to oxaliplatin, a first-line, standard-of-care CRC treatment. We generated oxaliplatin-resistant CRC tumor cells with clinically relevant dosing regimen, which displayed enhanced metastatic potential. Transcriptomic and phenotypic analyses revealed a critical function for cholesterol biogenesis in modulating TGF-{beta} signaling activity, which in turn regulates SERPINE1 expression, a gene we identified as a key player in promoting drug resistance and metastasis. Additionally, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that can predict overall and relapse-free survival (RFS) in clinical cohorts and is able to stratify patients into CMS4/iCMS3-fibrotic CRC-subtypes, underscoring its clinical utility. Using mouse tumor models, we provide further evidence that targeting SERPINE1 and cholesterol biogenesis can be viable approaches to re-sensitize the resistant pro-metastatic CRC cells to oxaliplatin. This study not only elucidates the molecular underpinnings of drug resistance and metastasis in primary CRC, but also offers prognostic and therapeutic strategies to guide clinical management of the disease. SignificanceThis study reveals critical resources and insights on oxaliplatin resistance and metastasis in CRC via a novel TGF-{beta} cholesterol axis. We generated improved oxaliplatin-resistant models that enabled identification of a prognostic SERPINE1-based gene signature to predict oxaliplatin resistance-induced metastasis in CRC. This gene signature derived from our models showed that the models can mimic CMS-4/iCMS-fibrotic-like metastatic CRC patients. We validated therapeutic candidates targeting CMS-4/iCMS-fibrotic-like metastatic CRC cells which can reverse drug resistance and metastasis.

cancer biology↗

A multi-model approach defines function altering MECP2 missense variants identified in individuals with autism spectrum disorder

Pathogenic variants in MECP2 commonly lead to Rett syndrome, where MECP2s function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also catalogued in individuals with autism spectrum disorder (ASD), including nine missense variants which had no known clinical significance at the start of this study. To assess these nine variants as risk alleles for ASD, we developed MECP2 variant functional assays using budding yeast and Drosophila. We calibrated these assays with known pathogenic and benign variants. Our data predict that four ASD variants are loss of function and five are functional. Protein destabilization offers insight into the altered function of some of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett pathogenic and ASD variants located in the methyl DNA binding domain that we analyzed proved to be loss of function, suggesting a clinically-relevant role for non-methyl DNA-binding by MECP2.

neuroscience↗