Histones are abundant nuclear proteins that are essential for the packaging of eukaryotic DNA into chromosomes. Different histone variants, in combination with their modification ‘code’, control regulation of gene expression in diverse cellular processes. Several enzymes that catalyze the addition and removal of multiple histone modifications have been discovered in the past decade, enabling investigations of their role(s) in normal cellular processes and diverse pathological conditions. This sudden influx of data, however, has resulted in need of an updated knowledgebase that compiles, organizes and presents curated scientific information to the user in an easily accessible format. Here, we present HIstome, a browsable, manually curated, relational database that provides information about human histone proteins, their sites of modifications, variants and modifying enzymes. HIstome is a knowledgebase of 55 human histone proteins, 106 distinct sites of their post-translational modifications (PTMs) and 152 histone-modifying enzymes. Entries have been grouped into 5 types of histones, 8 types of post-translational modifications and 14 types of enzymes that catalyze addition and removal of these modifications. The resource will be useful for epigeneticists, pharmacologists and clinicians. HIstome: The Histone Infobase is available online at http://www.iiserpune.ac.in/∼coee/histome/ and http://www.actrec.gov.in/histome/.

Histones through a complex repertoire of non-allelic variants and their post-translational modifications regulate gene expression. Though alterations in histone-modifying enzymes and post-translational modifications of histones have been studied in cancer, expression of histone variants has not been clearly associated with dedifferentiation and malignant transformation of hepatocyte in vivo. In the present work, the pattern of variants of histones was investigated during N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis. Our studies show for the first time in vivo overexpression of a major histone H2A variant H2A.1 and a decrease in H2A.2 at protein and mRNA levels by sodium dodecyl sulfate-Acetic acid-Urea-Triton (SDS-AUT) two-dimensional gel electrophoresis followed by matrix-assisted-laser desorption/ionization time-of-flight (TOF)/TOF mass spectrometry and reverse transcriptase-polymerase chain reaction analysis during sequential development of hepatocellular carcinoma (HCC). H2A.1 and H2A.2 are highly homologous, replication-dependent, non-allelic variants of histone H2A differing at only three amino acid positions. Our results of increase in proliferating cell nuclear antigen expression indicate that with increase in replicating population of transformed cells in HCC, H2A.1 expression increases, suggesting association of H2A.1 overexpression with hyper-proliferation of hepatocytes during cellular dedifferentiation and progressive transformation of normal liver to preneoplastic and neoplastic stages of HCC.

Cell extrusion is a morphogenetic process that is implicated in epithelial homeostasis and elicited by stimuli ranging from apoptosis to oncogenic transformation. To explore if the morphogenetic transcription factor, Snail (SNAI1), induces extrusion, we inducibly expressed a stabilized Snail6SA transgene in confluent MCF-7 monolayers. When expressed in small clusters (<3 cells) within otherwise wild-type confluent monolayers, Snail6SA expression induced apical cell extrusion. In contrast, larger clusters or homogenous cultures of Snail6SA cells did not show enhanced apical extrusion, but eventually displayed sporadic basal delamination. Transcriptomic profiling revealed that Snail6SA did not substantively alter the balance of epithelial: mesenchymal genes. However, we identified a transcriptional network that led to upregulated RhoA signalling and cortical contractility in Snail6SA expressing cells. Enhanced contractility was necessary, but not sufficient, to drive extrusion, suggesting that it collaborates with other factors. Indeed, we found that the transcriptional downregulation of cell-matrix adhesion cooperates with contractility to mediate basal delamination. This provides a pathway for Snail to influence epithelial morphogenesis independently of classic Epithelial to Mesenchymal Transition.