Biology subjects

Hawkins, R. D.

Publications and source records attributed to Hawkins, R. D..

5 recordsLinked to original sources

bioRxiv2023

Single neuron analysis of aging associated changes in learning reveals progressive impairmentsin transcriptional plasticity

Molecular mechanisms underlying aging associated impairments in learning and long-term memory storage are poorly understood. Here we leveraged the single identified motor neuron L7 in Aplysia, which mediates a form of non-associative learning, sensitization of the siphon-withdraw reflex, to assess the transcriptomic correlates of aging associated changes in learning. RNAseq analysis of the single L7 motor neuron isolated following short-term or long-term sensitization training of 8,10 and 12 months old Aplysia, corresponding to mature, late mature and senescent stages, has revealed progressive impairments in transcriptional plasticity during aging. Specifically, we observed modulation of the expression of multiple lncRNAs and mRNAs encoding transcription factors, regulators of translation, RNA methylation, and cytoskeletal rearrangements during learning and their deficits during aging. Our comparative gene expression analysis also revealed the recruitment of specific transcriptional changes in two other neurons, the motor neuron L11 and the giant cholinergic neuron R2 whose roles in long-term sensitization were previously not known. Taken together, our analyses establish cell type specific progressive impairments in the expression of learning- and memory-related components of the transcriptome during aging.

neuroscience↗

bioRxiv2022

Reconstructing the cascade of language processing in the brain using the internal computations of a transformer-based language model

Humans use complex linguistic structures to transmit ideas to one another. The brain is thought to deploy specialized computations to process these structures. Recently, a new class of artificial neural networks based on the Transformer architecture has revolutionized the field of language modeling, attracting attention from neuroscientists seeking to understand the neurobiology of language in silico. Transformers integrate information across words via multiple layers of structured circuit computations, forming increasingly contextualized representations of linguistic content. Prior work has focused on the internal representations (the "embeddings") generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into functionally-specialized "transformations" to provide a complementary window onto linguistic computations in the human brain. Using functional MRI data acquired while participants listened to naturalistic spoken stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent syntactic computations performed by individual, functionally-specialized "attention heads" differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers, contextual distances, and syntactic dependencies in a low-dimensional cortical space. Our findings indicate that large language models and the cortical language network may converge on similar trends of functional specialization for processing natural language.

neuroscience↗

bioRxiv2019

Single-cell analysis of Non-CpG methylation dynamics and gene expression in human oocyte maturation

Oocyte maturation is a coordinated process that is tightly linked to reproductive potential. A better understanding of gene regulation during human oocyte maturation will not only answer an important question in biology, but also facilitate the development of in vitro maturation technology as a fertility treatment. We generated single-cell transcriptome and use previously published single-cell methylome data from human oocytes at different maturation stages to investigate how genes are regulated during oocyte maturation, focusing on the potential regulatory role of non-CG methylation. DNMT3B, a gene encoding a key non-CG methylation enzyme, is one of the 1000 genes upregulated in mature oocytes, which may be at least partially responsible for the increased non-CG methylation as oocytes mature. Non-CG differentially methylated regions (DMRs) between mature and immature oocytes have multiple binding motifs for transcription factors, some of which bind with DNMT3B and may be important regulators of oocyte maturation through non-CG methylation. Over 98% of non-CG DMRs locate in transposable elements, and these DMRs are correlated with expression changes of the nearby genes. Taken together, this data indicates that global non-CG hypermethylation during oocyte maturation may play an active role in gene expression regulation, potentially through the interaction with transcription factors.

developmental biology↗

bioRxiv2018

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti

BackgroundThe mammalian inner ear is a complex morphological structure responsible for hearing and balance, and its pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics in the development and maturation of mouse inner ear sensory epithelium, we performed whole-genome bisulfite sequencing on inner ear tissue, yielding temporal base-pair resolution methylomes at key developmental time points.\n\nResultsWe found a late accumulation of non-CpG methylation, indicating a similarity between the inner ear sensory epithelium and neuronal tissue. Moreover, annotation of both unmethylated and low methylated regions pointed to regulatory elements active in the inner ear in proximity of and distal from transcriptional units. Finally, we identified differentially methylated regions across the transition periods. An analysis of these regions led us to identify several novel candidate regulatory factors, connecting regulatory elements from specific time points in development to molecular features that drive the development and maturation of the inner ear sensory epithelium. The GJB6 locus putative regulatory region was shown to upregulate distal GJB6 gene expression and a non-coding RNA.\n\nConclusionsOur analysis of inner ear sensory epithelium DNA methylation sheds light on novel regulatory regions in the hearing organ, and may help boost diagnostic capabilities and guide the development of therapeutics for hearing loss, by providing multiple intervention points for manipulation of the auditory system.

genomics↗

bioRxiv2018

An atlas of silencer elements for the human and mouse genomes

The study of gene regulation is dominated by a focus on the control of gene activation or controlling an increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have allowed for the global mapping of enhancer cis-regulatory elements, however, the identification of silencer elements by computational or experimental approaches in a genome-wide manner are lacking. We present a simple but powerful computational approach to identify putative silencers genome-wide. We used a series of consortia data to predict silencers in over 100 human and mouse cell or tissue types. We performed several analyses to determine if these elements exhibited characteristics expected of a silencers. Motif enrichment analyses on putative silencers determined that motifs belonging to known transcriptional repressors are enriched, as well as overlapping known transcription repressor binding sites. Leveraging promoter capture HiC data from several human and mouse cell types, we found that over 50% of putative silencer elements are interacting with gene promoters having very low to no expression. Next, to validate our silencer predictions, we quantified silencer activity using massively parallel reporter assays (MPRAs) on 7500 selected elements in K562 cells. We trained a support vector machine model classifier on MPRA data and used it to refine potential silencers in other cell types. We also show that similar to enhancer elements, silencer elements are enriched in disease-associated variants. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.

genomics↗