Mechanistic insights into the histone code and cytosine methylated DNA read-out and interpretation by chromatin associated modules

5-methyl cytosine (5mC) in DNA and, unmodified or covalent modifications on histone residues constitute the “epigenetic or histone code”. Epigenetic codes are read by ‘effector or reader’ modules that define the unique functional states of the chromatin. These codes provide signature for the ON or OFF of transcription, and DNA replication, repair and/ recombination. Mechanism of histone and methylated DNA codes read-out and interpretation can be understood from the two chromatin associated reader modules, which are discussed below.

Epigenetic marks, 5mC and histone 3 lysine 9 methylation (H3K9me), are required for heterochromatin formation and also transposon silencing. SUVH5 is a H3K9 methyltransferase and it is associated with the epigenetic silencing of the transposon. This module contains SET (H3K9me writer) and SRA (5mC reader) domains. We demonstrate that SRASUVH5 domain binds to 5mC-containing DNA in all sequence contexts (CG, CHG and CHH; H is C/A/T) present in plants. Our structure study demonstrates that SRASUVH5 employs a novel dual flip-out mechanism in 5mC recognition. Structure-based in vivo studies suggest that a functional SRASUVH5 domain is required for the accumulation of silencing marks, 5mC and H3K9me2, on the chromatin that contains the Ta3 transposon (Genes and Dev, 2011, 25:137-52).

Epigenetic mechanisms play crucial role in regulation of transcription of oncogenes and tumor suppressor genes. UHRF1, an E3-ubiquitin ligase, is required for the maintenance of CG methylation. Our recent discovery revealed that PHDUHRF1 finger is an unanticipated histone H3 unmodified Arginine 2 (H3R2um)-reader domain. Importantly, our binding and structure based functional studies showed that UHRF1’s ability to repress its target gene expression is dependent on PHDUHRF1 binding to H3R2um. PHDUHRF1 appears to be important for targeting the UHRF1 to euchromatic genes including tumor suppressor genes such as Axin2 and BMP4 (Mol Cell, 2011, 43: 275–284).