Characterization of novel histone methyltransferases and their roles in cancer

Abstract: Histone methyltransferases (HMTs) are epigenetic enzymes involved in numerous biological processes such as gene regulation. The majority of identified histone lysine methyltransferases (HKMTs) belongs to a large protein family defined containing an evolutionarily conserved catalytic domain, termed SET domain. In addition to SET domain-containing methyltransferases, a second large methyltransferase family has been identified. Structurally, this protein family is characterized by presence of a domain comprising a seven-membered β-sheet flanked by alpha-helices (Rossmann-fold). Members of this seven-β-strand family have been found to methylate numerous substrates including DNA, small molecules, arginine residues in histones, lysine residues in other proteins etc. For several years, DOT1L was the only of seven-β-strand family shown to methylate lysine 79 in histone H4. However, very recently, our lab identified a second HKMT among this family, which we termed KMT9. This finding suggested that other HKMTs might be present within the large seven-β-strand protein family. To identify additional HKMTs, we performed a cluster analysis of multiple amino acid sequence alignments of putative methyltransferase domains of the seven-β-strand family. The cluster analysis predicted five candidate proteins (METTL8, FAM86A, FAM86B1, FAM86B2, and TRMT9B) to be closely related to DOT1L and KMT9. HMT assays provided evidence that two candidates, FAM86A and TRMT9B, methylated core histones in vitro. Immunofluorescence assays revealed nuclear localization of TRMT9B, but detected FAM86A only in the cytoplasm. Additional assays revealed preferential methylation of histone H4 by TRMT9B. In addition, knock down of TRMT9B reduced migration of Ewing’s sarcoma and small cell lung carcinoma cells and deregulated expression of genes involved in extracellular matrix organization and cell adhesion. In summary, this work suggests that TRMT9B might be an important regulator of cancer cell migration. This hints at TRMT9B as a potential epigenetic target in cancer

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2019

Klassifikation und Themen

• Schlagwort: Epigenetik ; Histone

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2020
• Urheber: Duygu, Koca
• Beteiligte Personen und Organisationen: Schüle, Roland ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/154995
• URN: urn:nbn:de:bsz:25-freidok-1549955
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:51 MESZ