Biology subjects

Achiro, J. M.

Publications and source records attributed to Achiro, J. M..

3 recordsLinked to original sources

bioRxiv2025

Cytoplasmic and nuclear protein interaction networks of the synapto-nuclear messenger CRTC1 in neurons reveal cooperative chromatin binding between CREB1 and CRTC1, MEF2C and RFX3

Glutamatergic stimulation of excitatory neurons triggers the synapto-nuclear translocation of the cAMP response element (CRE) binding protein (CREB) regulated transcription coactivator 1 (CRTC1), resulting in the transcription of CREB1 target genes. Whether and how CRTC1 and CREB1 interact with other transcription factors to regulate activity-dependent transcription, and what the role of CRTC1 is in neurons beyond the activation of CREB1 regulated transcription, remains unknown. To address these questions in an unbiased manner, we used proximity labeling to identify CRTC1-proximal proteins in cytoplasmic and nuclear compartments of rodent forebrain neurons. The cytoplasmic CRTC1 proxisome included a variety of signaling pathways and downstream cellular processes involved in synaptic plasticity. In contrast, the nuclear CRTC1 proxisome included transcription factors that mediate activity-dependent transcription, chromatin factors, and splicing factors. Our data revealed that CRTC1 and CREB1 interact with MEF2C and RFX3 transcription factors in an activity-dependent manner. Thus, in chromatin immunoprecipitation-sequencing experiments, CREB1 was prebound to chromatin regions containing bZIP motifs in a manner that was unchanged by neuronal activity, while glutamatergic stimulation triggered the recruitment of CRTC1 and CREB1 to activity-dependent enhancers enriched in motifs for MEF2C and RFX3. Collectively, these results not only enhance our understanding of the role of cytoplasmic and nuclear CRTC1 in neurons, but also reveal a role for CRTC1 in promoting cooperativity of CREB1 with other transcription factors in response to synaptic activity.

neuroscience↗

bioRxiv2023

Aging Differentially Alters the Transcriptome and Landscape of Chromatin Accessibility in the Male and Female Mouse Hippocampus

Aging-related memory impairment and pathological memory disorders such as Alzheimers disease differ between males and females, and yet little is known about how aging-related changes in the transcriptome and chromatin environment differ between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus in both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response and synaptic function, and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic function. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE-1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Sex differences in gene expression and chromatin accessibility were amplified with aging, findings that may shed light on sex differences in aging-related and pathological memory loss. HighlightsO_LIAging amplifies sex differences in the transcriptome and chromatin accessibility of mouse hippocampus C_LIO_LIAging is associated with widespread changes in the transcriptome of mouse hippocampus, including in genes involved in immune response and synaptic function C_LIO_LIMyelin sheath-related genes in aged hippocampus show female-biased expression C_LIO_LIAlternative splicing of myelin sheath-related genes changes with aging in the hippocampus C_LIO_LISex-bias is evident in alternative splicing of nuclear and primary cilia genes C_LIO_LIAging in the hippocampus is associated with increased chromatin accessibility in both males and females C_LIO_LILINE-1 derived sequences are more accessible and LINE-1 transcripts are upregulated in the aged hippocampus of both males and females C_LIO_LIPromoter and CpG-rich regions show male-biased accessibility C_LI

neuroscience↗

bioRxiv2021

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

Activity-dependent gene expression is critical for synapse development and plasticity. To elucidate novel mechanisms linking neuronal activity to changes in transcription, we compared the nuclear proteomes of tetrodotoxin-silenced and bicuculline-stimulated cultured rodent neurons using nuclear-localized APEX2 proximity biotinylation and mass spectrometry. The tumor suppressor protein PDCD4 was enriched in the silenced nuclear proteome, and PDCD4 levels rapidly decreased in the nucleus and cytoplasm of stimulated neurons. The activity-dependent decrease of PDCD4 was prevented by inhibitors of both PKC and proteasome activity and by a phospho-incompetent mutation of Ser71 in the {beta}TRCP ubiquitin ligase-binding motif of PDCD4. We compared the activity-dependent transcriptomes of neurons expressing wildtype or degradation-resistant (S71A) PDCD4. We identified 91 genes as PDCD4 targets at the transcriptional level, including genes encoding proteins critical for synapse formation, remodeling, and transmission. Our findings indicate that regulated degradation of nuclear PDCD4 facilitates activity-dependent transcription in neurons.

neuroscience↗