Profiles

Celeste Greer, PhD

Research Interests

Forming a memory requires new messenger RNAs (mRNAs) to be produced in neurons via the process of gene transcription. Many human diseases and disorders that compromise cognition arise from mutations in transcriptional regulators, suggesting intellectual capacity and transcription are closely linked. By combining bioinformatics, molecular biology, and assays of behavior, the Greer lab is working towards a better understanding of the transcriptional mechanisms influencing learning and memory formation. We aim to use this information to understand, and potentially treat, transcriptional dysregulation in conditions such as neurodevelopmental disorders and Alzheimer’s disease. 

 We are currently pursuing the following hypotheses:

1. RNA polymerase II (RNAP2) is the complex that generates mRNAs from DNA. Looking at its binding patterns around memory-associated genes, after RNAP2 initiates transcription, it does not immediately generate a full-length mRNA. It pauses near the gene promoter and requires cellular signals to tell it to proceed to express the rest of the gene. After a neuron is stimulated, RNAP2 rapidly makes many mRNAs that help the neuron form new connections, and these mRNAs are critical for memory formation. While we know that transitioning from the paused state to productive elongation is fast, less is known about how this paused state is reinstated. We hypothesize that the rate of resetting this paused state may influence the rate of learning and are pursuing studies looking at the influence of pausing factors on behavior.
2. Our collaborators have identified that the transcription pause regulating factors we are investigating are expressed differently in human Alzheimer’s disease relative to cognitively normal controls in post-mortem brain tissue. We are following up on this finding by testing the hypothesis that transcription elongation is overly permissive in Alzheimer’s, and probing if drugs that alter transcriptional pausing might be effective for improving cognition in Alzheimer’s disease via this mechanism.
3. Transcription is influenced by changes to the histones that package cellular DNA, and enzymes that regulate these changes are frequently mutated in neurodevelopmental disorders. We are investigating how combinations of marks on histone tails and differences in how these modifications are distributed across genes influence gene expression in neurons. We hypothesize that understanding these changes to histones and the enzymes that regulate them can lead to a better understanding of the neurodevelopmental condition and facilitate the development of therapeutics.

Selected Publications

• Stefanelli G, Mokowski C, Brimble MA, Hall M, Reda A, Creighton SD, Leonetti AM, McLean TAB, Zakaria JM, Baumbach J, Greer CB, Davidoff AM, Walters BJ, Murphy PJ, Zovkic IB (2021). The histone chaperone Anp32e regulates memory formation, transcription, and dendritic morphogenesis by regulating steady-state H2A.Z binding in neurons. Cell Reports. 36(7): 119551. PMCID: PMC8422973.
• Greer CB, Wright J, Weiss JD, Lazarenko RM, Moran SP, Zhu J, Chronister KS, Jin AY, Kennedy AJ, Sweatt JD, Kaas GA (2021). Tet1 isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain. Journal of Neuroscience. 41(4): 578-593. PMCID: PMC7842754.
• Poplawski SG,^* Garbett KA,^* McMahan RL, Kordasiewicz HB, Zhao H, Kennedy AJ, Goleva SB, Sanders TH, Motley ST, Swayze EE, Ecker DJ, Sweatt JD, Michael TP,^# and Greer CB^# (2020). An antisense oligonucleotide leads to suppressed transcription of Hdac2 and long-term memory enhancement. Molecular Therapy - Nucleic Acids. 19: 1399-1412. PMCID: PMC7047133.
• Wesley CL, Greer CB, Chen JF, Arnal-Estape A, Cao J, Yan Q,^# and Nguyen DX^# (2020). Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain. BMC Medical Genomics. 13(1): 33. PMCID: PMC7060551.
• Collins BE, Sweatt JD, and Greer CB (2019). Broad domains of histone 3 lysine 4 trimethylation are associated with transcriptional activation in CA1 neurons of the hippocampus during memory formation. Neurobiology of Learning and Memory. 161: 149-157. PMCID: PMC6541021.
• Collins BE, Greer CB, Coleman BC, and Sweatt JD (2019). Review. Histone H3 lysine K4 methylation and its role in learning and memory. Epigenetics & Chromatin. 12: 7. PMCID: PMC6322263.
• Liao L, Alicea-Velázquez NL, Langbein L, Niu X, Cai W, Cho E, Zhang M, Greer CB, Debler EW, Yan Q, Cosgrove MS, Yang H (2018). High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical to the molecular and tumor suppressor functions of PBRM1. Molecular Oncology. 13, 811-828. PMCID: PMC6441893.
• Tan JL, Fogley RD, Flynn RA, Ablain J, Yang S, Saint-André V, Fan ZP, Do BT, Laga AC, Fujinaga K, Santoriello C, Greer CB, Kim YJ, Clohessy JG, Bothmer A, Pandell N, Avagyan S, Brogie JE, van Rooijen E, Hagedorn EJ, Shyh-Chang N, White RM, Price DH, Pandolfi PP, Peterlin BM, Zhou Y, Kim TH, Asara JM, Chang HY, Young RA, Zon LI (2016). Stress from nucleotide depletion activates the transcriptional regulator HEXIM1 to suppress melanoma. Molecular Cell. 62: 34-46. PMCID: PMC4836061.
• Greer CB, Tanaka Y, Kim YJ, Xie P, Zhang MQ, Park IH, and Kim TH (2015). Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery. Cell Reports. 13, 1444-1455. PMCID: PMC4934896.
• Kim YJ,^* Greer CB,^* Cecchini KR, Harris LN, Tuck DP, and Kim TH (2013). HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade. 32: 2828-2835. PMCID: PMC3676447.