Lukacs Laboratory

Home Lab Members Dendritic Cell Biology Early Life RSV Infection Epigenetics Mast Cell Biology & SCF Microbiome Contact Information
  1. Home
  2. Epigenetics

Epigenetics

Dll4 enhances Treg cell differentiation via activation of SMYD3 H3K4 methyltransferase leading to increased Foxp3.Epigenetic regulation of gene activation is the organization of loci into transcriptionally active or silent states altering the accessibility of transcription factors and polymerases to gene promoters and enhancers. Chromatin wound around histones is regulated by the nature of the modifications to the protein tails of the histone core components, including H2A, H2B, H3, and H4. These modifications include methylation, acetylation, ubiquitination, phosphorylation, etc, and determine the transcriptional status of the gene loci by exposing or sequestering the promoter region.  Methylation of lysines on histone H3, especially H3K4 trimethylation, is associated with transcriptional activation and has been the most frequently studied modification. This activation mark on H3K4 is offset by methylation of H3K9 and H3K27, which are associated with transcriptional silencing of the gene. These modifications rely on both methyltransferases that add methyl groups and demethylases that remove methyl groups from specific lysines allowing plasticity to gene activation. Thus, the specific regulation of genes by chromatin modifications is likely both gene and cell specific; however, what these specific modifications are and how they work in the epigenetic control of DC and T cells is only beginning to be understood.  Important, though, is the concept that histone modifications control access to gene promoters and enhancers for transcriptional regulation but do not directly activate genes. We have focused over the past several years on the alteration of both the T cell and DC that are epigenetically modified during RSV induced responses. Our publications have demonstrated that Smyd3, a H3K4 methyltransferase regulates Foxp3 expression through histone modification at the Foxp3 promoter and subsequently regulates RSV-induced immunopathology.  We have further taken a rational approach to determine the role of Dll4/Notch in regulation of Smyd3 induced Treg cells. SMYD3 was previously identified as an H3K4me3-specific histone methyltransferase that may be a proto-oncogene based upon its expression in numerous cancers and due to the altered cellular function observed in overexpression studies of normal cells or in cellular silencing studies of SMYD3 in tumors. We were the first to identify the function and regulation of SMYD3 in immune cells.  We have also shown that DC are epigenetically modified by the early life RSV infection. A key question has been whether the RSV infection and/or microbiome promote these innate immune cell changes.

 

 

Publications

  1. Malinczak CA, Fonseca W, Mire MM, Parolia A, Chinnaiyan A, Rasky AJ, Morris S, Yagi K, Bermick JR, Lukacs NW. Sex-associated Early-life viral Innate Immune Response is Transcriptionally Associated with chromatin remodeling of Type-I IFN-inducible Genes. Mucosal immunology 2023.
  2. Bermick JR, Issuree P, denDekker A, Gallagher KA, Santillan D, Kunkel S, Lukacs N, Schaller M. Differences in H3K4me3 and chromatin accessibility contribute to altered T-cell receptor signaling in neonatal naive CD4 T cells. Immunology and cell biology 2022; 100: 562-579.
  3. Malinczak CA, Parolia A, Fonseca W, Morris S, Rasky AJ, Bawa P, Zhang Y, Mire MM, Ziegler SF, Ptaschinski C, Chinnaiyan AM, Lukacs NW. TSLP-Driven Chromatin Remodeling and Trained Systemic Immunity after Neonatal Respiratory Viral Infection. Journal of immunology 2021; 206: 1315-1328.
  4. Ting HA, de Almeida Nagata D, Rasky AJ, Malinczak CA, Maillard IP, Schaller MA, Lukacs NW. Notch ligand Delta-like 4 induces epigenetic regulation of Treg cell differentiation and function in viral infection. Mucosal immunology 2018; 11: 1524-1536.
  5. Hrycaj SM, Marty-Santos L, Cebrian C, Rasky AJ, Ptaschinski C, Lukacs NW, Wellik DM. Hox5 genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion. Proceedings of the National Academy of Sciences of the United States of America 2018; 115: E10605-E10614.
  6. Ptaschinski C, Hrycaj SM, Schaller MA, Wellik DM, Lukacs NW. Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3. Journal of immunology 2017; 199: 501-509.
  7. Ptaschinski C, Mukherjee S, Moore ML, Albert M, Helin K, Kunkel SL, Lukacs NW. RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis In Vivo. PLoS pathogens 2015; 11: e1004978.
  8. Bermick JR, Lambrecht NJ, denDekker AD, Kunkel SL, Lukacs NW, Hogaboam CM, Schaller MA. Neonatal monocytes exhibit a unique histone modification landscape. Clinical epigenetics 2016; 8: 99.
  9. Nagata DE, Ting HA, Cavassani KA, Schaller MA, Mukherjee S, Ptaschinski C, Kunkel SL, Lukacs NW. Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal immunology 2015; 8: 1131-1143.