Mission Statement

The Cremins lab work at the spatial biology-technology interface to investigate the structure-function relationship of connections across the scales of chromatin, synapses, and circuits in normal neurophysiology and in neurological disorders. We pursue a multi-disciplinary approach integrating data across biological scales in the brain, including molecular Chromosome-Conformation-Capture sequencing technologies, single-cell imaging, optogenetics, genome engineering, induced pluripotent stem cell differentiation to neurons/organoids, in vitro and in vivo electrophysiological measurements, and via exciting collaborations with behaviorists.

Our long-term scientific goal is to dissect the fundamental mechanisms by which chromatin architecture causally governs genome function and, ultimately, long-term synaptic plasticity and neural circuit features in healthy mammalian brains as well as during the onset and progression of neurodegenerative and neurodevelopmental disease states. We seek to create a body of work known for its veracity, scientific excellence, and creative insights.

Our long-term mentorship goal is to develop a diverse cohort of next-generation scientific thinkers and leaders cross-trained in molecular and computational approaches. We seek to create a positive, high-energy environment with open and honest communication to empower individuals to discover and refine their purpose and grow into the best versions of themselves.

Projects in 2024 and beyond

To deliver on our primary mission, the members of the Cremins lab aim to pursue projects under the umbrella of the following central directions: 

  1. Synapse →  Nucleus: 
    Discover long-term activity-dependent chromatin changesin neural engrams in vivo and in neural analogs of learning in vitro
  2. Nucleus → Synapse: 
    Build single-cell and single-synapse technologies to dissect the causal relationship among chromatin, genome folding, RNA, and persistent synaptic features
  3. Synapse-resolution molecular neural connectome maps:
    Build new technologies for spatial insights in the brain: Retool paradigms from the 3D genome field to create molecular and functional maps of activity-dependent synaptic connectomes
  4. Chromatin control over genome instability:
    Elucidate the functional link between 3D genome miswiring, genome instability, and pathologic defects in synaptic plasticity in neurological disorders
  5. Genome Structure-Function:
    Develop tools to engineer chromatin for precise spatiotemporal control of gene expression states in healthy and diseased neurons
  6. Investigate when, how and why chromatin goes awry during the onset and progression of neurodevelopmental, neuropychiatric, and neurodegenerative disease states 
    We use disease as nature’s perturbation and focus on models of diseases known to involve both chromatin and synapse defects.

Contributions to-date: Insights into the genome’s structure-function relationship

At the lab’s inception (2014), it remained unclear how genomes are folded in the mammalian brain below Megabase-resolution, and whether and how higher-order structure could deterministically influence genome function. From 2014-2023, we:

  • We developed and applied new molecular and computational technologies to elucidate chromatin folding patterns at kilobase-resolution genome-wide, thus discovering that loops in cis and inter-chromosomal interactions in trans change substantially during neural lineage commitment, somatic cell reprogramming, stimulation of post-mitotic neurons, and in neurological disorders3,6,8,10,13-15,17,20-22,24,26,28,37,38. 
  • We demonstrated that cohesin-mediated loops are necessary for the establishment of new gene expression programs in post-mitotic neurons, including the upregulation of genes encoding axon guidance, dendritic spine morphology, and synaptic plasticity during neuron maturation in vivo as well as activity-dependent transcription during neural stimulation in vitro22,37.
  • We identified cohesin-mediated loops anchored by divergently-oriented CTCF binding sites that are necessary and sufficient for the firing efficiency and localization of human replication origins during S-phase re-entry after mitosis38. 
  • We discovered BREACHes (Beacons of Repeat Expansion Anchored by Contacting Heterochromatin): rare inter-chromosomal interactions connecting heterochromatinized synaptic genes susceptible to repeat instability in fragile X syndrome28.

Recent studies have called the functional role for folding into question based on the minimal effect of cohesin knock-down on the maintenance of pre-existing transcription43,44. Our major contribution through the end of 2023 has been to provide early foundational insights into the genome’s structure-function relationship1-42.

References

  1. Phillips, J.E. & Corces, V.G. CTCF: master weaver of the genome. Cell 137, 1194-211 (2009).
  2. Phillips-Cremins, J.E. & Corces, V.G. Chromatin insulators: linking genome organization to cellular function. Mol Cell 50, 461-74 (2013).
  3. Phillips-Cremins, J.E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281-95 (2013).
  4. Phillips-Cremins, J.E. Unraveling architecture of the pluripotent genome. Curr Opin Cell Biol 28, 96-104 (2014).
  5. Sauria, M.E., Phillips-Cremins, J.E., Corces, V.G. & Taylor, J. HiFive: a tool suite for easy and efficient HiC and 5C data analysis. Genome Biol 16, 237 (2015).
  6. Beagan, J.A. et al. Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming. Cell Stem Cell 18, 611-24 (2016).
  7. Beagan, J.A. & Phillips-Cremins, J.E. CRISPR/Cas9 genome editing throws descriptive 3-D genome folding studies for a loop. Wiley Interdiscip Rev Syst Biol Med 8, 286-99 (2016).
  8. Beagan, J.A. et al. YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment. Genome Res (2017).
  9. Norton, H.K. & Phillips-Cremins, J.E. Crossed wires: 3D genome misfolding in human disease. J Cell Biol 216, 3441-3452 (2017).
  10. Hsu, S.C. et al. The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries. Mol Cell 66, 102-116 e7 (2017).
  11. Rege, M. & Phillips-Cremins, J.E. Dynamic Looping Interactions: Setting the 3D Stage for the Macrophage. Mol Cell 67, 901-903 (2017).
  12. Dekker, J. et al. The 4D nucleome project. Nature 549, 219-226 (2017).
  13. Kim, J.H. et al. 5C-ID: Increased resolution Chromosome-Conformation-Capture-Carbon-Copy with in situ 3C and double alternating primer design. Methods 142, 39-46 (2018).
  14. Norton, H.K. et al. Detecting hierarchical genome folding with network modularity. Nat Methods 15, 119-122 (2018).
  15. Sun, J.H. et al. Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries. Cell (2018).
  16. Tam, O.H. et al. Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia. Cell Rep 29, 1164-1177 e5 (2019).
  17. Gilgenast, T.G. & Phillips-Cremins, J.E. Systematic Evaluation of Statistical Methods for Identifying Looping Interactions in 5C Data. Cell Syst 8, 197-211 e13 (2019).
  18. Huang, H. et al. A subset of topologically associating domains fold into mesoscale core-periphery networks. Sci Rep 9, 9526 (2019).
  19. Sizemore, A.E., Phillips-Cremins, J.E., Ghrist, R. & Bassett, D.S. The importance of the whole: Topological data analysis for the network neuroscientist. Netw Neurosci 3, 656-673 (2019).
  20. Kim, J.H. et al. LADL: light-activated dynamic looping for endogenous gene expression control. Nat Methods 16, 633-639 (2019).
  21. Zhang, H. et al. Chromatin structure dynamics during the mitosis-to-G1 phase transition. Nature 576, 158-162 (2019).
  22. Beagan, J.A. et al. Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression. Nat Neurosci 23, 707-717 (2020).
  23. Beagan, J.A. & Phillips-Cremins, J.E. On the existence and functionality of topologically associating domains. Nat Genet 52, 8-16 (2020).
  24. Fernandez, L.R., Gilgenast, T.G. & Phillips-Cremins, J.E. 3DeFDR: statistical methods for identifying cell type-specific looping interactions in 5C and Hi-C data. Genome Biol 21, 219 (2020).
  25. Wu, Y. et al. Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data. Nat Commun 11, 2061 (2020).
  26. Zhang, D. et al. Alteration of genome folding via contact domain boundary insertion. Nat Genet 52, 1076-1087 (2020).
  27. Pham, K., Nikish, A. & Phillips-Cremins, J.E. See(quence) and ye shall find: higher-order genome folding in intact single cells. Mol Cell 81, 1130-1132 (2021).
  28. Malachowski, T.. et al. Spatially coordinated heterochromatinization of autosomal synaptic genes in fragile X syndrome. Cell, (2023).
  29. Neuro, L.C. et al. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients. iScience 24, 103221 (2021).
  30. Dewan, R. et al. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Neuron 109, 448-460 e4 (2021).
  31. Maury, E.A. et al. Schizophrenia-associated somatic copy number variants from 12,834 cases reveal contribution to risk and recurrent, isoform-specific <em>NRXN1</em> disruptions. medRxiv, 2021.12.24.21268385 (2022).
  32. Park, D.S. et al. High-throughput Oligopaint screen identifies druggable regulators of genome folding. bioRxiv, 2022.04.08.487672 (2022).
  33. Sierra, I. et al. Remodeling and compaction of the inactive X is regulated by <em>Xist</em> during female B cell activation. bioRxiv, 2022.10.19.512821 (2022).
  34. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet 54, 412-436 (2022).
  35. Brown, A.L. et al. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature 603, 131-137 (2022).
  36. Cappelli, S. et al. NOS1AP is a novel molecular target and critical factor in TDP-43 pathology. Brain Commun 4, fcac242 (2022).
  37. Calderon, L. et al. Cohesin-dependence of neuronal gene expression relates to chromatin loop length. Elife 11(2022).
  38. Emerson, D.J. et al. Cohesin-mediated loop anchors confine the locations of human replication origins. Nature 606, 812-819 (2022).
  39. Girdhar, K. et al. Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains. Nat Neurosci 25, 474-483 (2022).
  40. Haws, S.A., Simandi, Z., Barnett, R.J. & Phillips-Cremins, J.E. 3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome. Cell 185, 2690-2707 (2022).
  41. Kwon, D.Y. et al. Neuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice. Nat Commun 13, 55 (2022).
  42. Naj, A.C. et al. Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus: The International Genomics of Alzheimer’s Project (IGAP). medRxiv, 2021.03.14.21253553 (2021).
  43. Rao, S.S.P. et al. Cohesin Loss Eliminates All Loop Domains. Cell 171, 305-320 e24 (2017).
  44. Hsieh, T.S. et al. Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1. Nat Genet 54, 1919-1932 (2022).

Our work is supported by the New York Stem Cell Foundation, the Alfred P. Sloan Foundation, the National Science Foundation, the National Institute of Mental Health, the National Institute of Neural Disorders and Stroke, the National Science Foundation (NSF), NIH Common fund initiatives, the Friedreich’s Ataxia Research Alliance, the Chan Zuckerberg Initiative (CZI), the Cure Huntington’s Disease Initiative (CHDI), and the NIH 4D Nucleome Common Fund Initiative.