Abstract. SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a major protein lysine methyltransferase trimethylating lysine 9 on histone

Regulation of X chromosome inactivation in mammals requires precise control of the levels of the non-coding RNA Xist. Almeida et al. describe an autoregulatory mechanism in which nascent Xist transcri...

Setdb1 suppresses tumor immunogenicity by repressing the expression of immunogenic genomic elements that can serve as tumor antigens and trigger an intracellular interferon loop. This work demonstrate...

The segregation of the genome into accessible euchromatin and histone H3K9-methylated heterochromatin helps silence repetitive elements and tissue-specific genes. In <i>Caenorhabditis elegans</i>, MET-2, the homologue of mammalian SETDB1, catalyzes H3K9me1 and me2, yet like SETDB1, its regulation is …

A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a kinact/KI of 1.0 × 106 M−1s−1 and demonstrates proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation occurs after treatment with UNC10013. Therefore, UNC10013 is a potent, selective, and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression. Design of cysteine-targeting analogs of

Heterochromatin plays a critical role in nuclear organization and the regulation of gene expression by directing 3D genome organization, regulating lineage-specific gene expression, and ensuring the r...

Abstract. SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a major protein lysine methyltransferase trimethylating lysine 9 on histone

Researchers have identified the enzyme SETDB1 as a key regulator in silencing transposable elements, preventing potential genomic instability and offering insights into therapeutic strategies for related diseases.

The H3K9me3-specific histone methyltransferase SETDB1 is critical for proper regulation of developmental processes, but the underlying mechanisms a...

Proceedings of the National Academy of Sciences, Volume 122, Issue 30, July 2025. SignificanceThe hippocampus, a brain region essential for learning and memory, undergoes neurogenesis throughout an individual’s lifespan. Adult neurogenesis relies on the proper generation of adult neural stem cells (aNSCs), which develop from embryonic ...

“Our team has demonstrated the presence of SETDB1 abnormalities, particularly its amplification, through WES analysis of osteosarcoma human samples and cell lines.”