Persistent chromatin loops shape gene expression plasticity upon stimulation and restimulation of human neurons

doi:10.1101/2025.09.30.679661

Persistent chromatin loops shape gene expression plasticity upon stimulation and restimulation of human neurons

2025 · doi:10.1101/2025.09.30.679661

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Persistent chromatin loops shape gene expression plasticity upon stimulation and restimulation of human neurons | bioRxiv /* */ /* */ red (N=100), red-->grey (N=29), grey-->red (N=624), grey-->grey (N=333). Persistently gained PE loops genes: red-->red (N=4), red-->grey (N=1), grey-->red (N=33), grey-->grey (N=12). We next considered genes with activity-independent, invariant gene expression (activity-invariant expression) across all key TTX and KCl stimulation timepoints. We found a roughly equal distribution of activity-invariant to upregulated (Grey➔Red), activity-invariant to invariant (Grey➔Grey), and activity-invariant to downregulated (Grey➔Blue) gene expression patterns by five days post-stimulation across looping classes and unlooped control genes ( Fig. 4F , Table S13 ). Ontology of activity-invariant genes at persistently gained PE loops that either stay invariantly expressed (Grey➔Grey) or are upregulated (Grey➔Red) five days post-stimulation revealed strong enrichment for pathways involved in synaptic signaling and neuronal function ( Fig. 4G ). Our results uncover the unexpected observation that persistent PE loops anchor activity-independent, invariantly expressed genes with ontology suggesting importance for neurophysiological pathways. Activity-invariant genes connected to activity-induced enhancers via persistent loops exhibit chromatin habituation upon second restimulation of human neurons Repetitive exposure to a common experience or stimulus contributes to the encoding and storage of memory. To simulate repetitive exposure in vitro , we re-stimulated our human neurons a second time with KCl five days after the original treatment ( Fig. 4H ). We used single-nucleus RNA-seq (snRNA-seq) to compare the proportion of cells expressing mRNA in single-stimulated versus double-stimulated neurons. To ensure the quality, rigor, and reproducibility of our snRNA-seq analysis, we filtered out low signal genes across condition, poor quality nuclei, and we normalized data across cells and conditions to account for technical artifacts ( Fig. S19, S20, Supplementary Methods ). We examined multiple gene expression classes for their single cell expression phenomena after second stimulation, including those that are (1) activity-invariant upon first KCl stimulation and become upregulated at five days post-single stimulation (Grey➔Red), (2) activity-invariant upon first KCl stimulation and remain invariant at five days post-single stimulation (Grey➔Grey), (3) activity-induced upon first KCl stimulation and remain persistently upregulated at five days post-single stimulation (Red➔Red), and (4) activity-induced upon first KCl stimulation but then return to baseline expression levels at five days post-single stimulation (Red➔Grey) ( Table S13 ). Two major observations emerged from our analysis of single-cell gene expression phenomena upon second KCl stimulation ( Fig. 4I ). Consistent with expectation, activity-upregulated genes (Red➔Grey or Grey➔Grey from first stimulation) can be re-induced after second stimulation when unlooped. However, when connected in persistently gained loops to activity-induced enhancers, we unexpectedly observe that the same classes of Red➔Red or Red➔Grey activity-upregulated genes exhibit a pattern of habituation in which they are not re-induced during second stimulation. We also unexpectedly observe that activity-independent, invariantly expressed synaptic genes (Grey➔Grey or Grey➔Red from first stimulation) can be downregulated only upon second stimulation when unlooped. By contrast, when anchoring persistently gained loops, such Grey➔Grey or Grey➔Red genes unexpectedly escape from downscaling and can even become activity-upregulated at second stimulation. Our data reveal that persistent activity-gained loops exhibit two types of compensatory gene expression phenomena, both protection from downscaling and habituation, after repeated pharmacological stimulation. CTCF binding is linked to persistent H3K27ac at activity-induced enhancers anchoring persistently gained loops at five days post-stimulation in human neurons A notable observation from exploring the functional effects of persistently lost and persistently gained loops on gene expression is that in large part the loops were devoid of CTCF occupancy ( Fig. 3G , Fig. S21 ). Having demonstrated the functional impact of non-CTCF loops, we also investigated the functional role for CTCF-mediated loops on activity-dependent gene expression in human neurons. We stratified putative activity-induced enhancers at our various PE loop classes into those with and without CTCF and assessed the H3K27ac signal changes over time, as histone modifications have been hypothesized as a substrate for cellular memory ( 89 , 90 ). In support of this hypothesis, murine studies have demonstrated that histone lysine acetylation specifically contributes to memory formation in learning paradigms ( 46 , 91 - 94 ). In a study using fear conditioning, mouse engram cells exhibited a persistent increase in H3K27ac at four enhancers tested, even in the absence of continued stimulus ( 43 ). We therefore assessed whether activity-induced changes in H3K27 acetylation persisted five days after stimulation genome-wide ( Fig. 5 ). Download figure Open in new tab Fig. 5: Persistent histone modification H3K27ac at putative non-coding activity-induced enhancers bound by CTCF loop to promoters with persistent activity-upregulated gene expression. (A) Heatmaps of H3K27ac CUT&Tag at non-coding activity-induced enhancers, comparing TTX, 2 hours and 5 days post-stimulation, and log2(fold change) of 5 days/TTX. (B) Schematic representation of four strata of persistent memory of activity-induced H3K27ac peaks. (C-D) CTCF-bound versus non-CTCF-bound activity-induced enhancers tested for association with persistent traces of H3K27ac versus no H3K27ac 5 days later. Odds ratios and Pvalues (Fisher’s Exact Test). (C) Odds ratios across a titration of the degree of H3K27ac persistence at CTCF and no CTCF bound enhancers for each loop class and unlooped enhancers are shown. (D) Odds ratios, bootstrapped 95% confidence intervals, and Pvalues for tests for each loop class and unlooped enhancers shown. (E) Looped versus unlooped activity-induced enhancers tested for association with persistent traces of H3K27ac versus no H3K27ac 5 days later. Odds ratios, bootstrapped 95% confidence intervals, and Pvalues (Fisher’s Exact Test) for tests for each loop class vs. unlooped enhancers after stratifying by CTCF occupancy by enhancers are shown. (F) Persistent gain looped versus unlooped activity-induced genes tested for association with persistent upregulation 5 days later (top). Persistent gain looped versus unlooped activity-induced genes tested for association with de-activation 5 days later (bottom). Odds ratios, bootstrapped 95% confidence intervals, and Pvalues (Fisher’s Exact Test) for tests for genes looped to memory and non-memory enhancers are shown. We focused our analysis on putative activity-induced enhancers, defined as non-coding H3K27ac peaks gained de novo at 2 hours after KCl stimulation and not present in neurons only treated with TTX ( Fig. 5A ). We unexpectedly observed that a subset of activity-induced enhancers binding retained an enduring trace of H3K27ac signal at 5 days after KCl stimulation ( Fig. 5A ). We noticed that those enhancers with possible memory of H3K27ac were also strongly bound by CTCF. By contrast, activity-induced enhancers not bound by CTCF largely showed H3K27ac signal that returned to baseline levels at 5 days post-stimulation ( Fig. 5A ). Our data suggest that putative activity-induced enhancers with CTCF binding are more likely to retain persistent traces of activity-dependent H3K27ac compared to those without CTCF. To test the relationship between CTCF binding and persistent H3K27ac memory, we stratified the putative activity-induced enhancers into three levels of persistence (high, medium, and low) and no persistence (no memory) based on the H3K27ac signal in neurons 5 days post KCl stimulation ( Fig. 5B , Supplementary Methods ). We then evaluated the association between CTCF binding at the putative activity-induced enhancers for each class of loop and persistent versus non-persistent H3K27ac ( Supplementary Methods ) ( Fig. 5C ). We demonstrate a statistically significant association between CTCF occupancy and H3K27ac persistence at activity-induced enhancers ( Fig. 5C-D ). The Odds Ratio effect size titrates by the strength of the H3K27ac persistence ( Fig. 5C ). Our analyses confirm our qualitative observations that CTCF binding is associated with a higher probability of enduring traces of H3K27ac at activity-induced enhancers at 5 days post-stimulation. We assessed whether looping alone was associated with persistent H3K27ac at activity-induced enhancers. Using the most stringent persistent H3K27ac strata, we compared the looped enhancers from each looping class against unlooped enhancers matched by CTCF occupancy status. We did not find consistent, significant associations with persistent H3K27ac at activity-induced enhancers and looping ( Fig. 5E ). Our data suggest that CTCF occupancy at activity-induced enhancers regardless of looping or unlooped status contributes to persistence in H3K27ac at activity-induced enhancers. Finally, we asked if CTCF-bound activity-induced enhancers with enduring traces of H3K27ac have an effect on mRNA expression levels of the promoters connected in loops. We observed a significant enrichment between persistently gained loops with enduring traces of H3K27ac at activity-induced enhancers and activity-induced genes upon first KCl stimulation that remain persistently upregulated at five days post-single stimulation (Red➔Red) ( Fig. 5F ). No other gene expression class ( Figs. 3 - 4 ) was notably enriched at persistently gained loops with persistent activity-induced enhancers. Taken together, our data reveal a link among persistent loops, enduring traces of H3K27ac at activity-induced enhancers, and persistent upregulation of activity induced gene expression. Discussion Here, using an in vitro human model of hiPSC-derived neurons, we identify a link between pharmacological stimulation of action potential firing and persistent changes to chromatin and gene expression. We identify activity-induced and activity-decommissioned chromatin loops connecting promoters to distal putative enhancers marked by noncoding activity-dependent H3K27ac signal. Persistently lost loops are associated with sustained, activity-downregulation of gene expression ( Fig. 6A , top ), whereas persistently gained loops are enriched for activity-induced gene expression that resumes baseline levels by five days post-stimulation ( Fig. 6A , bottom ). We identify a subset of persistently gained promoter-enhancer loops that maintain enduring traces of the H3K27ac histone mark at enhancers ( Fig. 6B ). The promoters looped to enduring activity-induced enhancers exhibit activity-induced gene expression that remains persistently high for five days after removal of the initial stimulation ( Fig. 6B , top ). Together, our results indicate that higher-order chromatin structure is plastic upon pharmacological stimulation of action potentials, and that persistent traces of structural chromatin memory exist for at least five days after removal of the stimulus. Download figure Open in new tab Fig. 6: Link among persistent chromatin loops and plasticity in activity-dependent and - independent gene expression during a timecourse of stimulation and re-stimulation of human neurons. (A) Persistent activity-lost loops are enriched for activity-downregulated gene expression that remains persistently downregulated 5 days after simulation (top). Persistent activity-gained loops are enriched for activity-upregulated gene expression at the expected time point of 3-6 hours after stimulation, but the expression resumes to levels close to baseline by 5 days post-stimulation (bottom). (B) We identified a small subset of persistent activity-gained loops connecting enhancers to promoters of activity-upregulated genes that remain persistently upregulated at 5 days post-stimulation (top). The putative non-coding enhancers are bound by CTCF and exhibit enduring traces of the histone modification H3K27ac. (C) We treated human neurons to a second stimulation and measured the proportion of cells with detectable mRNA levels. Persistent activity-gained loops (red) exhibit two types of compensatory gene expression phenomena after repeated pharmacological stimulation. Activity-upregulated genes are re-induced after second stimulation when unlooped. By contrast at persistently gained loops, the activity-upregulated genes exhibit habituation and are not induced during second stimulation. Moreover, activity-independent, invariantly expressed synaptic genes are downregulated only upon second stimulation when unlooped. If anchoring persistently gained loops, such genes unexpectedly escape from downscaling and become activity-upregulated at second stimulation. Recent studies demonstrate that DNA methyltransferases are required for memory formation and consolidation in murine models ( 78 , 79 ), suggesting that activity-induced changes in DNA methylation might also play an important role in learning and memory. Furthermore, studies using in vitro and in vivo model systems and bulk DNA methylation assays have demonstrated dynamic changes in DNA methylation upon neural stimulation ( 78 - 84 , 95 , 96 ). However, activity-induced patterns of DNA methylation at regulatory elements anchoring chromatin looping have not yet been explicitly defined in human post-mitotic neurons. Classic foundational studies have demonstrated that regulatory elements bound by CTCF are refractory to DNA methylation at promoters of developmentally regulated and imprinted genes ( 85 - 87 ). Here, we find that a near negligible minor fraction of both promoters and enhancers anchoring loops exhibit dynamic changes in DNA methylation upon neural stimulation. Moreover, we find that differentially methylated CpG loci (DMLs) almost exclusively occur at promoters and enhancers devoid of CTCF occupancy. Our observations are consistent with our working model that CTCF protects looped promoters and enhancers from dynamic activity-dependent DNA methylation changes during the stimulation of human neurons. A general model of memory posits that the repetitive exposure to a common experience or stimulus, such as multiple training events during learning ( 48 , 97 , 98 ), continued use of a drug in addiction ( 99 - 101 ), or repeated exposure to aversive stimuli leading to trauma ( 102 , 103 ), underlies aspects of the encoding and storage of memory. To explore molecular correlates of the repetitive induction of action potential firing in human neurons, we re-exposed human neurons to a second round of KCl stimulation five days after the first treatment. We uncovered major, unexpected observations. First, activity-inducible genes were robustly restimulated upon second KCl exposure when unlooped. By contrast, activity-inducible genes connected to activity-inducible enhancers in persistently gained PE loops failed to upregulate upon re-stimulation, suggesting a form of chromatin habituation ( Fig. 6C , top ). Second, we identified a large subset of activity-independent, invariantly expressed synaptic genes. Although invariantly expressed on first stimulation, a subset of these genes responded to re-stimulation by further up regulation or severe down regulation when unlooped. By contrast, when anchoring persistently gained PE loops, activity-independent synaptic genes could be activity-stimulated and protected from the phenomena of chromatin downscaling in human neurons ( Fig. 6C , bottom ). Our data reveal a link between the persistence of chromatin structure and the plasticity of gene expression patterns, including chromatin downscaling and habituation, over time and in response to multiple exposures of a stimulus in human neurons. It is established that organisms can reduce their response to a repetitive stimulus through habituation ( 104 ) and neuronal circuits can downscale their synaptic connections and strength upon repeated activity ( 105 ). Here, we observe striking parallels at the biological scale of the nucleus with phenomena of gene expression habituation and downscaling in human post-mitotic neurons. Our data are consistent with a model in which persistently gained loops protect genes from extreme expression up or downregulation upon second stimulation. Overall, our work reports the unexpected phenomena of persistent structural traces in the form of activity dependent higher-order chromatin loops and suggest that loop persistence shapes how the mammalian neural genome remodels, remembers and responds over time and across multiple stimulations. Future work integrating phenomena of chromatin and gene expression persistence with synapse and circuit physiology in vivo will shed important new light into the molecular and cellular mechanisms governing long-term memory storage. Funding New York Stem Cell Foundation Robertson Investigator (NYSCF-R-124; J.E.P-C) NIH NIMH (2R01MH120269; J.E.P-C) NIH NINDS (1R01NS114226; J.E.P-C) NSF CAREER Award (CBE1943945; J.E.P-C) 4D Nucleome Common Fund (1U01DK127405; J.E.P-C) 4D Nucleome Common Fund (1U01DA052715; J.E.P-C) NIH Common Fund / NIMH (1DP1MH129957; J.E.P-C) PA Department of Health – CURE (2020F07; J.E.P-C) CZI Neurodegenerative Disease Pairs Award (DAF2022-250430; J.E.P-C) CZI Neurodegenerative Disease Pairs Award (DAF2022-250577; J.E.P-C) NIH Shared Instrumentation Grant (1S10OD032363; J.E.P-C) Cure Huntington’s Disease Initiative (CHDI; ID A-18744, to J.E.P-C) NSF Emerging Frontiers Research Innovation (EFMA19-33400; JEPC) NIH F30 (F30HD114405; K.P.) NIH F31 (F31HG014082; R.P.) Author contributions Conceptualization: AJW, AN, JEPC Formal Analysis: AJW, KP, KRT, CL, KRC, PX, RP Methodology: AJW, KP, KRT, CL, KRC, HSR, RB Visualization: AJW, KP, CL Investigation: AJW, AN, KP, HSR, SM Funding acquisition: JEPC Project administration: JEPC Writing: AJW, KP, TP, JEPC Competing Interests The authors of this work have no competing interests. Data and materials availability All data is provided at GEO under the accessions: GSEXXXA (snm3c), GSEXXXB (CUT&Tag), GSEXXXC (RNA-seq), GSEXXXD (ChIP-seq) and GSEXXXE (snRNA-seq), and all data and code will be available upon publication. Supplementary Materials Materials and Methods Supplementary Text Figs. S1 to S21 Tables S1 to S13 Acknowledgements We thank Tim Pollex, Rahul Sureka, Harshini Chandrashekar, and all members of the Cremins lab for helpful discussions. We thank Rahul Sureka and Gui Hu for assistance with sequencing. K. Pham is the recipient of a F30 Training Grant. K. Titus is the recipient of a Fontaine fellowship. A. Nikish is the recipient of an NIH T32 Training grant. H. Ryu is the recipient of the Michael S. Brown Graduate Research Fellowship. R. Patel is the recipient of an F31 Training Grant. J. E. Phillips-Cremins was a New York Stem Cell Foundation Robertson Investigator and an Alred P. Sloan Foundation Fellow during this project. We thank the UPenn Cell and Developmental Biology Core (RRID SCR_022373) and the Children’s Hospital of Philadelphia Flow Cytometry Core Laboratory (RRID: SCR_009726) for providing instrumentation. We acknowledge the NIH S10 grant funding mechanism (J.E.P-C) for supporting the MEA equipment used to generate neurophysiology measurements in this manuscript. Funder Information Declared U.S. National Science Foundation, https://ror.org/021nxhr62 , CBE1943945 , EFMA19-33400 National Institute of Mental Health , 2R01MH120269 , 1DP1MH129957 , 1S10OD032363 National Human Genome Research Institute , F31HG014082 NIH Office of the Director , 1U01DK127405 , 1U01DA052715 National Institute of Neurological Disorders and Stroke , 1R01NS114226 New York Stem Cell Foundation , NYSCF-R-124 Pennsylvania Department of Health , 2020F07 Chan Zuckerberg Initiative (United States), https://ror.org/02qenvm24 , DAF2022-250430 , DAF2022-250577 Cure Huntington's Disease Initiative , ID A-18744 National Institute of Child Health and Human Development , F30HD114405 References and Notes 1. ↵ T. J. Jarome , F. D. Lubin , Epigenetic mechanisms of memory formation and reconsolidation . Neurobiol Learn Mem 115 , 116 – 127 ( 2014 ). OpenUrl CrossRef PubMed 2. ↵ M. Kyrke-Smith , J. M. Williams , Bridging Synaptic and Epigenetic Maintenance Mechanisms of the Engram . 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