Biology subjects

Solano, A.

Publications and source records attributed to Solano, A..

9 recordsLinked to original sources

bioRxiv2026

SMCHD1's DNA binding activity enables its stable retention on chromatin

Chromatin proteins play critical roles in gene regulation, yet frequently we do not fully understand how weak DNA binding affinity of such proteins contributes to their locus-specific actions. Here, we studied SMCHD1, a non-canonical SMC-family protein involved in three-dimensional genome organization and gene repression of the inactive X chromosome and its autosomal targets. We replaced endogenous SMCHD1 with GFP-tagged wild-type or hinge-domain DNA-binding mutant SMCHD1 to define the cellular role of DNA binding. The mutant showed reduced enrichment at the inactive X chromosome in female cells, while retaining stable binding at most autosomal binding sites. Impaired DNA binding weakens SMCHD1-mediated gene repression and chromatin-state regulation, producing hypomorphic effect. Multiple live-cell imaging methods reveal that DNA binding constrains SMCHD1 mobility and supports maintenance, rather than initial recruitment, of chromatin-bound SMCHD1 both during interphase and mitosis. Thus, SMCHD1's weak and sequence-independent DNA binding is a key determinant of its chromatin residence, localization and function. Our findings provide a framework for understanding SMCHD1 and other chromatin proteins with sequence-independent DNA binding activity.

genomics↗

bioRxiv2025

Benchmarking long-read RNA-sequencing technologies with LongBench: a cross-platform reference dataset profiling cancer cell lines with bulk and single-cell approaches

Long-read RNA sequencing enables full-length transcript profiling and improved isoform resolution, but variable platforms and evolving chemistries demand careful benchmarking for reliable application. We present LongBench, a matched, multi-platform reference dataset spanning bulk, single-cell, and single-nucleus transcriptomics across eight human lung cancer cell lines with synthetic spike-in controls. LongBench in-corporates three state-of-the-art long-read protocols alongside Illumina short reads: Oxford Nanopore Technologies (ONT) PCR-cDNA, ONT direct RNA, and PacBio Kinnex. We systematically evaluate transcript capture, quantification accuracy, differential expression, isoform usage, variant detection, and allele-specific analyses. Our results show high concordance in gene-level differential analyses across protocols, but reduced consistency for transcript-level and isoform analyses due to length- and platform-dependent biases. Single-cell long-read data are highly concordant with bulk for high-confidence features, though single-nuclei data show reduced feature detection. LongBench provides one of the largest publicly available long-read benchmarking resources, enabling rigorous cross-platform evaluation and guiding technology selection for transcriptomic research.

genomics↗

bioRxiv2025

Epidermal γδ T cells, CD8 T cells and macrophages are increased in number in alopecia areata and express BST2 as part of an interferon-driven antiviral gene signature

Alopecia areata is an autoimmune disorder affecting approximately 2% of the global population, characterized by immune-mediated disruption of hair follicle immune privilege and unpredictable hair loss. While CD4 and CD8 T cells are established drivers of pathogenesis, the roles of other immune cell populations remain incompletely defined. Here, we reaffirm the pathogenic role of CD8 T cells and identify a contribution of epidermal {gamma}{delta} T cells and macrophages to alopecia areata. Using publicly available single-cell RNA sequencing (scRNAseq) data from the skin of C3H/HeJ mice with alopecia areata, we demonstrate that epidermal {gamma}{delta} T cells upregulate genes associated with immune homeostasis, proliferation, and inflammation, including BST2, an interferon-stimulated antiviral protein. In vivo, epidermal {gamma}{delta} T cells and keratinocytes are increased in number, with BST2 expression enriched around hair follicles. BST2 is also expressed on CD8 T cells actively producing IFN-{gamma} and on CD11b+ macrophages with signatures of antiviral and complement system pathways. In human alopecia areata skin, BST2 expression is elevated in alopecia areata and downregulated following treatment with the JAK inhibitor tofacitinib. Together, these findings position BST2 as a marker of interferon-driven immune activation and highlight epidermal {gamma}{delta} T cells as a contributor to alopecia areata pathogenesis.

immunology↗

bioRxiv2025

A mouse model of Adams-Oliver Syndrome reveals defective Notch1 signaling in endothelial cells as a driver of pathogenesis

Adams-Oliver Syndrome (AOS) is a rare congenital disorder characterized by scalp, limb, and cardiovascular defects. While variants in the NOTCH1 receptor, DLL4 ligand, and RBPJ transcription factor have been implicated in AOS, the driving tissue types and molecular mechanisms by which these variants cause pathogenesis are unknown. Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA. Consistent with this idea, mice carrying an AOS-associated Rbpj allele develop dominant phenotypes that include lethality and cardiovascular defects in a Notch1 heterozygous background, whereas Notch1 and Rbpj compound heterozygous null alleles are well-tolerated. To facilitate studies into the key tissues driving AOS pathogenesis, we employed conditional genetics to isolate the contribution of the vasculature to the development of AOS-like phenotypes. Importantly, our studies show that expression of the Rbpj AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects. These data establish that defective Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model.

developmental biology↗

bioRxiv2024

The human hippocampus is involved in implicit motor learning

Recent evidence suggests that the human hippocampus, traditionally associated with declarative memory, plays a role in motor sequence learning (MSL). However, the classic MSL paradigm depends initially on declarative learning. Therefore, it is critical to discern whether the participation of the hippocampus relates to its canonical role or to processing a general aspect of learning that transcends the declarative/non-declarative distinction. To address this issue, here we turn to visuomotor adaptation -a type of motor learning involving skill recalibration-which unlike MSL can be easily manipulated to eliminate the explicit component. Here, we examined the broader involvement of the hippocampus in procedural motor learning by using diffusion MRI to indirectly assess structural plasticity associated with memory consolidation in visuomotor adaptation (VMA) and an implicit-only version (IVMA). We found that both VMA and IVMA engaged the left posterior hippocampus in a learning-specific manner. Remarkably, while VMA induced only transient hippocampal alterations, IVMA elicited structural changes that persisted overnight, underscoring the reliance on implicit learning for enduring neuroplasticity. As expected, training on both visuomotor tasks impacted the microstructure of the cerebellum, the motor and the posterior parietal cortex. Notably, the temporal dynamics of changes in these regions closely paralleled those of the left hippocampus, suggesting that motor and limbic regions operate in a coordinated manner as part of the same neural network. Collectively, our findings support an active role of the hippocampus in procedural motor memory and argue for a unified function in memory encoding regardless of the declarative or non-declarative nature of the task.

neuroscience↗

bioRxiv2023

Consolidation of sensorimotor adaptation depends both on the passage of time and sleep

Contrary to its well-established role in declarative learning the impact of sleep on motor memory consolidation remains a subject of debate. Motor learning involves skill acquisition and skill maintenance, two critical aspects in achieving movement precision. Current literature suggests that whereas motor skill acquisition benefits from sleep, consolidation of skill maintenance depends solely on the passage of time. This has led to the proposal that skill maintenance may be an exception to other types of memories. Here, we address this ongoing controversy in humans through three comprehensive experiments. We found that when training occurs throughout the day consolidation of skill maintenance proceeds independently of sleep. However, when it takes place closely before bedtime so that sleep aligns with the memory stabilization window, a 30% memory enhancement emerges along with a distinct modulation of neural markers of sleep consolidation. Our findings reconcile seemingly conflicting perspectives on the active role of sleep in procedural motor learning, and offer the potential to accelerate motor recovery in rehabilitation programs through the synchronization of training sessions with sleep.

neuroscience↗

bioRxiv2021

Visuomotor adaptation modulates the clustering of sleep spindles into trains

Sleep spindles are thought to promote memory consolidation. Recently, we have shown that visuomotor adaptation (VMA) learning increases the density of spindles and promotes the coupling between spindles and slow oscillations, locally, with the level of spindle-SO synchrony predicting overnight memory retention. Yet, growing evidence suggests that the rhythmicity in spindle occurrence may also influence the stabilization of declarative and procedural memories. Here, we examined if VMA learning promotes the temporal organization of sleep spindles into trains. We found that VMA increased the proportion of spindles and spindle-SO couplings in trains. In agreement with our previous work, this modulation was observed over the contralateral hemisphere to the trained hand, and predicted overnight memory retention. Interestingly, spindles grouped in a cluster showed greater amplitude and duration than isolated spindles. The fact that these features increased as a function of train length, provides evidence supporting a biological advantage of this temporal arrangement. Our work opens the possibility that the periodicity of NREM oscillations may be relevant in the stabilization of procedural memories. CONTRIBUTION STATEMENTEver since the discovery of memory systems, the study of the mechanisms supporting the consolidation of declarative and procedural memories has progressed somewhat in parallel. We now know, however, that structures originally thought of as purely declarative such as the hippocampus, participate in the consolidation of procedural tasks. Recently, we showed that sleep predicts long-term motor memory through the local synchrony between fast sleep spindles and slow oscillations, a mechanism initially described for the consolidation of declarative memories. Novel evidence has linked the rhythmicity in the occurrence of spindles to memory stabilization. This framework proposes that temporally clustered spindles into trains of two or more separated by 3-6 seconds, may favor the reinstatement and subsequent reprocessing of previously acquired memories. This temporal arrangement may facilitate mnemonic replay and neocortical integration. In the present study, we show that motor learning promotes the organization of spindles into trains, locally, over the contralateral hemisphere, and that this modulation predicts overnight memory retention. Spindle grouping also augmented the proportion of spindle-SO couplings in trains. Importantly, spindles in a cluster increased their duration and amplitude as a function of train length, pointing to a physiological benefit of this temporal organization.

neuroscience↗

bioRxiv2021

Pro-inflammatory Cytokine GM-CSF Improves Learning/Memory and Brain Pathology in Dp16 Down Syndrome Mice and Improves Learning/Memory in Wild-Type Mice

Down syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) improved cognition and reduced biomarkers of brain pathology in humans with Alzheimers disease (AD), another inflammatory disorder, and in a mouse model of AD. To investigate the effects of GM-CSF treatment on DS/ID, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that GM-CSF treatment improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology and aggregation and fewer calretinin-positive interneurons, both of which were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population.

neuroscience↗

bioRxiv2020

Local coupling between sleep spindles and slow oscillations supports the consolidation of motor memories

Recent studies from us and others suggest that traditionally declarative structures (e.g., hippocampus) mediate some aspects of the encoding and consolidation of procedural memories. This evidence points to the existence of converging physiological pathways across memory systems. Here, we examined whether the coupling between slow oscillations (SO) and spindles, a mechanism well established in the consolidation of declarative memories, is relevant for the stabilization of human motor memories. To this aim, we conducted an EEG study in which we quantified various parameters of these oscillations during a night of sleep that took place immediately after learning a visuomotor adaptation task. We hypothesized that if this coupling is instrumental to motor memory consolidation then spindles locked to the active phase of a slow oscillation would predict long-term memory. We found that visuomotor adaptation increased the overall density of fast ([≥]12 Hz) but not slow (<12Hz) spindles during NREM3. This modulation was manifested rather locally, over the hemisphere contralateral to the trained hand. Although motor learning did not affect the density of SOs, it substantially enhanced the number of fast spindles locked to the active phase of SOs. The fact that only coupled spindles of the left hemisphere predicted long-term memory overnight, points to the precise phase relationship between these oscillations as a fundamental signature of motor memory consolidation. Our work provides evidence in favor of a common mechanism at the basis of the stabilization of declarative and non-declarative memories. Significance StatementEver since the discovery of memory systems, the study of the mechanisms supporting the consolidation of declarative and procedural memories has progressed somewhat in parallel. In the last few years, however, this framework is starting to change. We now know that structures originally thought of as purely declarative, such as the hippocampus, participate in the consolidation of procedural tasks. Here, we show that sleep modulates the stabilization of motor memories through a mechanism involved in the consolidation of declarative memories, based on the local synchrony between fast sleep spindles and slow oscillations. The fact that only coupled -but not uncoupled- spindles of the contralateral hemisphere predicted long-term memory supports a role of this association in the consolidation of motor memories.

neuroscience↗