Research Article

Differential roles of trithorax protein MLL-1 in regulating neuronal Ion channels

Sonya Dave and An Zhou*

Published: 08 September, 2021 | Volume 5 - Issue 2 | Pages: 089-093

Repressive regulation of potassium channel genes by Polycomb group (PcG) proteins contributes to PcG protein-mediated neuroprotection against neuronal ischemic injury, as seen in an ischemic stroke. Here we asked the question whether Trithorax group (TrxG) proteins, the antagonistic partners of PcG proteins (i.e, epigenetic activators targeting the same genes) may also regulate potassium channels. Results of patch-clamp studies on cultured neuronal cells showed that inhibition of TrxG protein MLL-1 led to an increase in potassium channel activity, an unexpected effect for a presumed gene activator. In contrast, decreased sodium currents were observed with MLL-1 inhibition. Increased or decreased levels of potassium channel protein Kv2.1 or sodium channel protein Nav1.2, respectively, were seen with MLL-1 inhibition, as determined by immunocytochemistry. These results, for the first time, demonstrate an involvement of TrxG protein MLL-1 in regulating neuronal ion channels, potentially repressing potassium channel genes.

Read Full Article HTML DOI: 10.29328/journal.jnnd.1001057 Cite this Article Read Full Article PDF


MLL-1; Epigenetics; Polycomb group proteins; Trithorax group proteins; Repressor; Potassium channel; Ischemic stress


  1. Hernandez-Encarnacion L, Sharma P, Simon R, Zhou A. Condition-specific transcriptional regulation of neuronal ion channel genes in brain ischemia. Int J Physiol Pathophysiol Pharmacol. 2017; 9: 192-201. PubMed: https://pubmed.ncbi.nlm.nih.gov/29348796/
  2. Stapels M, Piper C, Yang T, Li M, Stowell C, et al. Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci Signal. 2010; 3: ra15. PubMed: https://pubmed.ncbi.nlm.nih.gov/20197544/
  3. Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington CA, et al. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet. 2003; 362: 1028-1037. PubMed: https://pubmed.ncbi.nlm.nih.gov/14522533/
  4. Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006; 20: 1123-1136. PubMed: https://pubmed.ncbi.nlm.nih.gov/16618801/
  5. Brand M, Nakka K, Zhu J, Dilworth FJ. Polycomb/Trithorax Antagonism: Cellular Memory in Stem Cell Fate and Function. Cell Stem Cell. 2019; 24: 518-533. PubMed: https://pubmed.ncbi.nlm.nih.gov/30951661/
  6. Geisler SJ, Paro R. Trithorax and Polycomb group-dependent regulation: a tale of opposing activities. Development. 2015; 142: 2876-2887. PubMed: https://pubmed.ncbi.nlm.nih.gov/26329598/
  7. Koch L. Gene regulation: Yin and Yang of Polycomb/Trithorax response elements. Nat Rev Genet. 2014; 15: 644-645. PubMed: https://pubmed.ncbi.nlm.nih.gov/25159600/
  8. Mills AA. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer. 2010; 10: 669-682. PubMed: https://pubmed.ncbi.nlm.nih.gov/20865010/
  9. Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell. 2007; 128: 735-745. PubMed: https://pubmed.ncbi.nlm.nih.gov/17320510/
  10. Simon RP, Meller R, Zhou A, Henshall D. Can genes modify stroke outcome and by what mechanisms? Stroke. 2012; 43: 286-291. PubMed: https://pubmed.ncbi.nlm.nih.gov/22156698/
  11. O'Bryant Z, Leng T, Liu M, Inoue K, Vann KT, et al. Acid Sensing Ion Channels (ASICs) in NS20Y cells - potential role in neuronal differentiation. Mol Brain. 2016; 9: 68. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920985/
  12. Sirianni MJ, Fujimoto KI, Nelson CS, Pellegrino MJ, Allen RG. Cyclic AMP analogs induce synthesis, processing, and secretion of prepro nociceptin/orphanin FQ-derived peptides by NS20Y neuroblastoma cells. DNA Cell Biol. 1999; 18: 51-58. PubMed: https://pubmed.ncbi.nlm.nih.gov/10025508/
  13. Zhou A, Minami M, Zhu X, Bae S, Minthorne J, et al. Altered biosynthesis of neuropeptide processing enzyme carboxypeptidase E after brain ischemia: molecular mechanism and implication. J Cereb Blood Flow Metab. 2004; 24: 612-622. PubMed: https://pubmed.ncbi.nlm.nih.gov/15181368/
  14. Ansari KI, Kasiri S, Mandal SS. Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo. Oncogene. 2013; 32: 3359-3370. PubMed: https://pubmed.ncbi.nlm.nih.gov/22926525/
  15. Chan AKN, Chen CW. Rewiring the Epigenetic Networks in MLL-Rearranged Leukemias: Epigenetic Dysregulation and Pharmacological Interventions. Front Cell Dev Biol. 2019; 7: 81. PubMed: https://pubmed.ncbi.nlm.nih.gov/31157223/
  16. Heddleston JM, Wu Q, Rivera M, Minhas S, Lathia JD, et al. Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ. 2012; 19: 428-439. PubMed: https://pubmed.ncbi.nlm.nih.gov/21836617/
  17. Papale M, Ferretti E, Battaglia G, Bellavia D, Mai A, et al. EZH2, HIF-1, and Their Inhibitors: An Overview on Pediatric Cancers. Front Pediatr. 2018; 6: 328. PubMed: https://pubmed.ncbi.nlm.nih.gov/30510924/
  18. Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015; 525: 206-211. PubMed: https://pubmed.ncbi.nlm.nih.gov/26331536/
  19. Malik B, Hemenway CS. CBX8, a component of the Polycomb PRC1 complex, modulates DOT1L-mediated gene expression through AF9/MLLT3. FEBS Lett. 2013; 587: 3038-3044. PubMed: https://pubmed.ncbi.nlm.nih.gov/23891621/
  20. Kingston RE, Tamkun JW. Transcriptional regulation by trithorax-group proteins. Cold Spring Harb Perspect Biol. 2014; 6: a019349. PubMed: https://pubmed.ncbi.nlm.nih.gov/25274705/
  21. Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. Cell. 2017; 171: 34-57. PubMed: https://pubmed.ncbi.nlm.nih.gov/28938122/
  22. Cosgrove MS, Patel A. Mixed lineage leukemia: a structure-function perspective of the MLL1 protein, FEBS J. 2010; 277: 1832-1842. PubMed: https://pubmed.ncbi.nlm.nih.gov/20236310/
  23. McCarthy N. Leukaemia: MLL makes friends and influences. Nat Rev Cancer. 2010; 10: 529. PubMed: https://pubmed.ncbi.nlm.nih.gov/20677349/
  24. Wang Z, Song J, Milne TA, Wang GG, Li H, et al. Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell. 2010; 141: 1183-1194. PubMed: https://pubmed.ncbi.nlm.nih.gov/20541251/
  25. Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ. MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein. Proc Natl Acad Sci U S A., 2003; 100: 8342-8347. PubMed: https://pubmed.ncbi.nlm.nih.gov/12829790/ 


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