Biology subjects

Sakib, M. S.

Publications and source records attributed to Sakib, M. S..

11 recordsLinked to original sources

bioRxiv2025

lncRNA 3222401L13Rik/ENSG00000272070 modulates microglial inflammatory programs in association with PU.1

Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA 3222401L13Rik as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog ENSG00000272070. We found that 3222401L13Rik is expressed in both astrocytes and microglia and increases with age. Knockdown of 3222401L13Rik in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNF, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog ENSG00000272070 showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, 3222401L13Rik interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, ENSG00000272070 expression was significantly reduced in postmortem Alzheimers disease (AD) brains, and AD-associated genes were enriched among 3222401L13Rik-regulated targets. Together, our results identify 3222401L13Rik/ENSG00000272070 as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests 3222401L13Rik as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases. HighlightsO_LI3222401L13Rik is a glia-enriched long non-coding RNA regulating microglial state C_LIO_LIKnockdown of 3222401L13Rik increases TNF signaling C_LIO_LIThe human homolog ENSG00000272070 shows reduced expression in AD brains C_LIO_LI3222401L13Rik interacts with the AD-associated transcription factor PU.1 C_LIO_LIA conserved 3222401L13Rik-PU.1 axis modulates microglial inflammation in aging and disease C_LI

neuroscience↗

bioRxiv2025

NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease

The increasing evidence that non-coding RNAs can become deregulated during pathogenesis is dramatically expanding the space for drug discovery beyond the protein-coding genome. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular function, yet most remain uncharacterized. Here, we identify a previously unstudied lncRNA, which we named Neuronal Identity (NeuID)--a conserved, brain-enriched transcript expressed exclusively in neurons. NeuID is downregulated in the brains of Alzheimers disease (AD) patients. Mechanistically, NeuID maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of NeuID disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated NeuID overexpression restores neuronal function in A{beta}42-treated neurons. These findings identify NeuID as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD. One sentence summaryWe identify NeuID, a novel brain and neuron-specific long non-coding RNA downregulated in Alzheimers disease, as a key regulator of neuronal identity and a promising therapeutic target to restore neuronal function.

neuroscience↗

bioRxiv2024

LncRNA 3222401L13Rik Is Up-regulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3

Aging is linked to a decline in cognitive functions and significantly increases the risk of neurodegenerative diseases. While molecular changes in all central nervous system (CNS) cell types contribute to aging-related cognitive decline, the mechanisms driving disease development or offering protection remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular functions and gene expression, yet their roles in aging, particularly within glial cells, are not well characterized. In this study, we investigated lncRNA expression profiles in non-neuronal cells from aged mice. We identified 3222401L13Rik, a previously unstudied lncRNA enriched in glial cells, as being specifically upregulated in astrocytes during aging. Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes essential for neuronal support and synapse organization. This function was also conserved in human iPSC-derived astrocytes. Additionally, we found that 3222401L13Rik mediates its cellular effects through interaction with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and that overexpression of Npas3 effectively rescued the functional deficits observed in astrocytes lacking 3222401L13Rik. Our findings suggest that upregulation of 3222401L13Rik in aging astrocytes acts as a compensatory mechanism to enhance neuronal and synaptic support, potentially delaying the onset of molecular and structural changes in both astrocytes and neurons. Strategies to boost 3222401L13Rik expression earlier in life may help mitigate age-associated loss of neuronal plasticity.

neuroscience↗

bioRxiv2023

Bioengineering of a human innervated cardiac muscle model

Cardiac autonomic neurons control cardiac contractility. Dysregulation of the autonomic nervous system can lead to sympathetic overdrive resulting in heart failure and an increased incidence of fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a novel model of neuro-cardiac junctions, constructed by fusion of a bioengineered neural organoid (BENO) patterned to autonomic nervous system and engineered human myocardium (EHM). Projections of sympathetic neurons into engineered human myocardium formed presynaptic terminals in close proximity to cardiomyocytes and an extensive vascular network co-developing in the tissues. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functionality of neuro-cardiac junctions in iEHM. This model will serve as a human surrogate system to delineate neuron and cardiac cell contribution to brain and heart diseases and is an important step towards engineering a human brain to heart axis in a dish.

bioengineering↗

bioRxiv2023

A single-cell transcriptomic analysis of the mouse hippocampus after voluntary exercise

Exercise has been recognized as a beneficial factor for cognitive health, particularly in relation to the hippocampus, a vital brain region responsible for learning and memory. Previous research has demonstrated that exercise-mediated improvement of learning and memory in humans and rodents correlates with increased adult neurogenesis and processes related to enhanced synaptic plasticity. Nevertheless, the underlying molecular mechanisms are not fully understood. With the aim to further elucidate these mechanisms we provide a comprehensive dataset of the mouse hippocampal transcriptome at the single-cell level after four weeks of voluntary wheel-running. Our analysis provides a number of interesting observations. For example, the results suggest that exercise affects adult neurogenesis by accelerating the maturation of a subpopulation of Prdm16-expressing neurons. Moreover, we uncover the existence of an intricate crosstalk among multiple vital signaling pathways such as NF-{kappa}B, Wnt/{beta}-catenin, Notch, retinoic acid (RA) pathways altered upon exercise in a specific cluster of excitatory neurons within the Cornu Ammonis (CA) region of the hippocampus. In conclusion, our study provides an important resource dataset and sheds further light on the molecular changes induced by exercise in the hippocampus. These findings have implications for developing targeted interventions aimed at optimizing cognitive health and preventing age-related cognitive decline.

neuroscience↗

bioRxiv2022

Conserved reduction of m6A marks during aging and neurodegeneration is linked to altered translation of synaptic transcripts

N6-methyladenosine (m6A) plays diverse roles in the regulation of mRNA metabolism. In the mammalian brain it has been linked to developmental processes and memory function. However, the precise role of m6A in the context synaptic plasticity and especially during impaired cognition are not fully understood. Here, we describe the mouse and human brain m6A epi-transcriptome in a tissue-specific manner. We furthermore show that m6A levels undergo a massive decrease across mouse brain regions as a consequence of aging. In addition, Alzheimer's disease in humans correlates with decreased N6-methylation in a similar population of transcripts that are linked to synaptic function and localized to synapses, such as the calcium/calmodulin-dependent kinase II (CaMKII). We furthermore show that reduced m6A levels impair synaptic protein-synthesis of CAMKII. Our results suggest that m6A-RNA-methylation is an important mechanism to control synaptic protein synthesis which is affected early in cognitive diseases. Significance statementThe addition of N6-methyladenosine (m6A) to RNA plays a role in various cellular processes and its de-regulation has been linked to several devastating diseases. The precise role of m6A RNA-methylation in the adult brain is, however, not well understood. In our study, we describe the genome-wide m6A epi-transcriptome in the healthy and diseased brains of mice and humans. Our data demonstrate that a substantial amount of m6A transcripts are conserved. These transcripts are linked to the regulation of synaptic processes and are localized to synapses. In the diseases brain we detect RNA hypomethylation across multiple transcripts in all investigated brain regions and across species. At the mechanistic level we find that reduced m6A levels specifically impairs synaptic protein-synthesis.

neuroscience↗

bioRxiv2021

Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

neuroscience↗

bioRxiv2021

H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion by activating TRNP1 expression

Increase in the size of human neocortex, acquired in evolution, accounts for the unique cognitive capacity of humans. This expansion appears to reflect the evolutionarily-enhanced proliferative ability of basal progenitors (BPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, whether or how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP amplification and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Mechanistically, H3K9ac drives BP amplification by increasing expression of the evolutionarily regulated gene, TRNP1, in the developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture. One Sentence SummaryH3K9ac promotes basal progenitor amplification, neocortex expansion and gyrification by activating TRNP1 expression in evolution.

developmental biology↗

bioRxiv2020

SETD1B controls cognitive function via cell type specific regulation of neuronal identity genes

Histone-3-lysine-4-methylation (H3K4me) is mediated by six different lysine methyltransferases (KMTs). Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to intellectual disability but its role in the adult brain has not been studied yet. Here we show that mice lacking Setd1b from excitatory neurons of the adult forebrain exhibit severe memory impairment. By combining neuron-specific ChIP-seq, RNA-seq and single cell RNA-seq approaches we show that Setd1b controls the expression of neuronal-identity genes with a broad H3K4me3 peak linked to learning and memory processes. Our data furthermore suggest that basal neuronal gene-expression is ensured by other H3K4 KMTs such as Kmt2a and Kmt2b while the additional presence of Setd1b at the single cell level provides transcriptional consistency to the expression of genes important for learning & memory.

neuroscience↗

bioRxiv2020

Epigenetic gene-expression links heart failure to memory impairment

In current clinical practice care of diseased patients is often restricted to separated disciplines. However, such an organ-centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age-associated dementias. The underlying molecular mechanisms are presently unknown and thus corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms we show that heart failure leads to specific changes in hippocampal gene-expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.

neuroscience↗

bioRxiv2019

Epigenetic mechanism of carbohydrate sulfotransferase 3 (CHST3) downregulation in the aging brain

Neural extracellular matrix (ECM) is a complex molecular meshwork surrounding neurons and glial cells in the extracellular space. Structural and functional state of ECM in the brain is tightly regulated by various components of neural ECM such as hyaluronic acid, chondroitin sulfate proteoglycans, link proteins, tenascins, various matrix-modifying enzymes such as chondroitin sulfate synthases and carbohydrate sulfotransferase together with matrix-degrading enzymes. Age-dependent accumulation of ECM molecules is implicated in the age-associated decline in synaptic and cognitive functions. Understanding age-associated changes in the expression of genes involved in regulating various components of ECM can provide an insight into the role of ECM in the aging brain. Hence, in this study, we compared the expression levels of ECM regulating genes in three groups of mice: 2-3 months old mice (2-3M), 22- to 26-month-old mice (22-26M) and more than 30-month-old mice (>30M). Using qPCR, we discovered that in the hippocampus of >30M old mice, the majority of ECM related genes are downregulated, while genes related to neuroinflammation are highly upregulated. This pattern was accompanied by a decrease in cognitive performance of the >30M old mice and was most correlated among ECM-related genes with the downregulation of carbohydrate sulfotransferase 3 (CHST3) gene expression. Interestingly, in 24-26M mice, no general decrease in the expression of ECM related genes was observed, although we still found the upregulation in neuroinflammatory genes and downregulation of CHST3. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of CHST3 gene in non-neuronal (NeuN-negative) but not in neuronal (NeuN-positive) cells. We conclude that in 22-26 M old brains there are minor changes in expression of the studied bona fide neural ECM genes but there is a prominent epigenetic dysregulation of the CHST3 gene responsible for 6-sulfation of chondroitin sulfates, which may lead to impaired brain plasticity and cognitive decline.

neuroscience↗