Analysis of the Hox epigenetic code

Abstract

Archetypes of histone modifications associated with diverse chromosomal states that regulate access to DNA are leading the hypothesis of the histone code (or epigenetic code). However, it is still not evident how these post-translational modifications of histone tails lead to changes in chromatin structure. Histone modifications are able to activate and/or inactivate several genes and can be transmitted to next generation cells due to an epigenetic memory. The challenging issue is to identify or "decrypt" the code used to transmit these modifications to descent cells. Here, an attempt is made to describe how histone modifications operate as part of histone code that stipulates patterns of gene expression. This papers emphasizes particularly on the correlation between histone modifications and patterns of Hox gene expression in Caenorhabditis elegans . This work serves as an example to illustrate the power of the epigenetic machinery and its use in drug design and discovery.

HOX genes in stem cells: Maintaining cellular identity and regulation of differentiation

“…Demethylation of H3K27 in turn can induce the expression of the hitherto repressed (lineage-specific) HOX genes ( Bernstein et al, 2006 ; Soshnikova and Duboule, 2008 ). These chromosomal domains marked either by an active H3K4 or silent H3K27 turned out to be crucial to establish an epigenetic memory (including the HOX genes) of the cellular identity in stem cells and moreover following differentiation ( Ringrose and Paro, 2007 ; Kim et al, 2010 ; Ezziane, 2012 ). The simultaneous expression of a certain combination of HOX genes (termed the “HOX-code”) further on was presented to be tissue-specific ( Kessel and Gruss, 1991 ), as HOX genes impose positional identity to developing tissues ( Mallo et al, 2010 ).…”

Methylation in HOX Clusters and Its Applications in Cancer Therapy

“…Histone modifications also affect the assembly and restructuration of the nucleosome [ 9 , 10 ]. This fundamental repeat unit of the chromatin corresponds to an octamer of four core histone proteins (H2A, H2B, H3 and H4) wrapped twice around the DNA molecule ( Figure 2 ) [ 11 ].…”

“…A wide variety of enzymes participate in these processes such as acetyltransferases, deacetylases, methyltransferases, demethylases and kinases. All these enzymes work in concert with ATP-dependent chromatin-remodeling complexes that recognize specific histone modifications, affecting the disassembly and assembly of nucleosomes and the movement of histone octamers along the DNA [ 10 ].…”

Homeobox genes gain trimethylation of histone H3 lysine 4 in glioblastoma tissue

“…The homeobox genes contain a particular DNA sequence that encodes the homeodomain. The products of the homeobox genes play key roles in regulating development [ 11 ]. They often appear in clusters [ 22 ].…”

“…Elevated levels of H3K4me3 were also observed in MRI-classified GBM of the subventricular zone in Papio anubis [ 10 ]. The H3K4 methyltransferases, such as MLL and SMYD3, were found closely associated with GBM [ 11 , 12 ]. MLL can directly activate the homeobox gene HOXA10 and contributes to the tumorigenic potential of glioblastoma stem cells [ 13 ].…”