Biology subjects

Motiwala, A.

Publications and source records attributed to Motiwala, A..

6 recordsLinked to original sources

bioRxiv2026

Xist expression in male Peromyscus leucopus is associated with restricted chromatin repression and incomplete X-to-autosome dosage compensation

X-chromosome inactivation (XCI) equalizes X-linked gene dosage between XX females and XY males in eutherian mammals and is canonically initiated by the long noncoding RNA Xist, which coats one X chromosome and recruits Polycomb-mediated chromatin silencing. Xist expression has therefore been considered female-specific and central to balancing gene dosage between two X chromosomes in females and a single X chromosome in males. However, emerging evidence suggests that Xist can also be expressed in male cells in both healthy and pathogenic contexts, raising fundamental questions about the scope and constraints of Xist function. Here, we identify robust Xist expression in somatic cells of male white-footed deermice (Peromyscus leucopus), a placental mammal with a conventional XY karyotype. Unlike the chromosome-wide Xist RNA coating observed in females, male Xist RNA localizes as discrete nuclear puncta and is detected across multiple tissues by RNA-seq, RT-qPCR, and RNA fluorescence in situ hybridization. Integrative transcriptomic and chromatin profiling using CUT&Tag and single-nucleus Paired-Tag reveals that male Xist expression is not merely incidental but has measurable regulatory consequences. In females, Xist expression is associated with chromosome-wide enrichment of the repressive histone mark H3K27me3 and transcriptional silencing of X-linked genes. In males, although Xist transcription is also associated with H3K27me3, this interaction does not induce global X-chromosome inactivation. Instead, Xist selectively represses a subset of dosage-sensitive neural and mitochondrial X-linked genes, while the majority of X-linked genes remain largely active. Notably, with persistent Xist activity, neither males nor females achieve complete X-to-autosome dosage compensation in P. leucopus. These findings establish P. leucopus as a mammalian system in which male Xist operates outside the canonical female-specific XCI pathway, revealing a gene-selective model of X-chromosome regulation. Our results challenge the universality of prevailing XCI models and suggest that partial, context-dependent Xist activity represents a viable and evolutionarily stable dosage compensation strategy in mammals. Author SummaryIn mammals, females and males differ in their sex chromosome: females have two X chromosomes, while males have one. This difference creates a potential imbalance in gene dosage, which can disrupt development if not properly controlled. Typically, females compensate by turning off one chromosome through a process called X-chromosome inactivation (XCI), which is triggered by the long noncoding RNA Xist. In parallel, a process known as X-to-autosome dosage compensation balances X-linked gene expression relative to the rest of the genome. Because XCI occurs in females, Xist has long been considered to function only in female cells and be inactive in males. Here, we show that Xist is persistently expressed in male white-footed deermice (Peromyscus leucopus), a cricetid rodent with a conventional XY sex chromosome system. Unlike the large Xist RNA "cloud" that covers the inactive X chromosome in females, Xist RNA in males appears as small, discrete spots in the nucleus. By combining gene expression and chromatin profiling, we find that male Xist associates with the repressive histone mark H3K27me3 but does not switch off the entire X chromosome. Instead, Xist in males selectively reduces the activity of a limited set of X-linked genes, while most X-linked genes remain active. Surprisingly, we also find that neither male nor female P. leucopus achieves complete balance between X-linked and autosomal gene expression, despite the long-held view that such balance is essential for mammalian viability. By uncovering functional Xist activity in males of a non-model species and demonstrating incomplete dosage compensation in both sexes, this work challenges the traditional view of XCI as a strictly female-specific strategy and reveals an unexpected flexibility in how mammals regulate the X chromosome.

genetics↗

bioRxiv2025

Dermal fibroblast cultures recapitulate differences between deermice and mice in responses to a Toll-like receptor agonist

The white-footed deermouse Peromyscus leucopus is a primary reservoir for the agents of Lyme disease and other zoonoses in North America and manifests infection tolerance for the bacteria, protozoa, and viruses it hosts. In previous in vivo studies P. leucopus and M. musculus differed in the degree of sickness and profiles of biomarkers after exposure to bacterial lipopolysaccharide, a TLR4 agonist. As an approach for assessing immunity of mammals in nature and for longitudinal studies of colony animals in the laboratory, we evaluated using bulk and single cell RNA-seq primary dermal fibroblast cultures of P. leucopus and M. musculus in their short-term responses to a TLR2 agonist lipopeptide. By single cell RNA-seq cultures of both species comprised at least two types of fibroblasts, which were further differentiated in their responses to TLR agonists. With continued passage the mouse cell population lost viability, while the deermouse cell population spontaneously transformed into a cell line stably maintained under standard conditions. Bulk RNA-seq revealed distinctive profiles for deermouse and mouse cells in arginine metabolism gene expression, high baseline transcription of the antioxidant transcription factor Nfe2l2 (Nrf2) in deermouse fibroblasts, and the transcription of the aging-associated cytokine interleukin-11 in agonist-treated mouse fibroblasts but not deermouse fibroblasts. In both species cultures there was increased transcription of several types of endogenous retrovirus (ERV) and transposable elements (TE) after exposure to the agonist. The transcribed ERV/TE sequences in M. musculus cells were generally longer in length and with greater potential for translation than sequences in treated P. leucopus cells. The results indicate feasibility of this in vitro model for both laboratory- and field-based studies and that inherent differences between deermice and mice in cell-autonomous innate immune responses and ERV/TE activation can be demonstrated in dermal fibroblasts as well as the animals themselves.

immunology↗

bioRxiv2024

A posture subspace in primary motor cortex

To generate movements, the brain must combine information about movement goal and body posture. Motor cortex (M1) is a key node for the convergence of these information streams. How are posture and goal information organized within M1s activity to permit the flexible generation of movement commands? To answer this question, we recorded M1 activity while monkeys performed a variety of tasks with the forearm in a range of postures. We found that posture- and goal-related components of neural population activity were separable and resided in nearly orthogonal subspaces. The posture subspace was stable across tasks. Within each task, neural trajectories for each goal had similar shapes across postures. Our results reveal a simpler organization of posture information in M1 than previously recognized. The compartmentalization of posture and goal information might allow the two to be flexibly combined in the service of our broad repertoire of actions.

neuroscience↗

bioRxiv2024

Dynamical constraints on neural population activity

The manner in which neural activity unfolds over time is thought to be central to sensory, motor, and cognitive functions in the brain. Network models have long posited that the brains computations involve time courses of activity that are shaped by the underlying network. A prediction from this view is that the activity time courses should be difficult to violate. We leveraged a brain-computer interface (BCI) to challenge monkeys to violate the naturally-occurring time courses of neural population activity that we observed in motor cortex. This included challenging animals to traverse the natural time course of neural activity in a time-reversed manner. Animals were unable to violate the natural time courses of neural activity when directly challenged to do so. These results provide empirical support for the view that activity time courses observed in the brain indeed reflect the underlying network-level computational mechanisms that they are believed to implement.

neuroscience↗

bioRxiv2023

Dorsolateral striatum encodes a temporal basis for the organization of behavior

To behave adaptively, the brain must register temporal structure in the environment and use it to organize behavior. The dorsolateral striatum (DLS) integrates sensorimotor input, and is necessary for accurate timing and structuring behavior in general. However, if DLS provides the basis for mapping temporal features in the environment to behavior, its activity should predict variation in that mapping. A reanalysis of DLS population activity in rats comparing the duration of two sequentially presented vibratory stimuli revealed a striking correspondence between neural activity and behavior. Varying vibration intensity of the second stimulus induced systematic biases in temporal judgments, and corresponding biases in multiple features of DLS activity during stimulus presentation, including population coding of time. In contrast, the same intensity manipulations applied to the first stimulus affected neither behavior nor neural activity. Furthermore, neuronal response profiles were best described as a continuum, arguing against hypotheses where categories of responses, e.g., ramping activity, selectively underpin temporal processing. These data represent important additional evidence that striatal population dynamics support the organization of behavior by mapping temporal information to action.

neuroscience↗

bioRxiv2020

Dopamine responses reveal efficient coding of cognitive variables

Reward expectations based on internal knowledge of the external environment are a core component of adaptive behavior. However, internal knowledge may be inaccurate or incomplete due to errors in sensory measurements. Some features of the environment may also be encoded inaccurately to minimise representational costs associated with their processing. We investigate how reward expectations are affected by differences in internal representations by studying rodents behaviour and dopaminergic activity while they make time based decisions. Several possible representations allow a reinforcement learning agent to model animals choices during the task. However, only a small subset of highly compressed representations simultaneously reproduce, both, animals behaviour and dopaminergic activity. Strikingly, these representations predict an unusual distribution of response times that closely matches animals behaviour. These results can inform how constraints of representational efficiency may be expressed in encoding representations of dynamic cognitive variables used for reward based computations.

neuroscience↗