Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known ifthe oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.

Cdc6, which alters chromatin ultrastructure to allow DNA replication in muscle stem cells transitioning out of quiescence, is identified as a target of the MyoD transcription factor.

Background: Thrombosis is the fatal and disabling consequence of cardiovascular diseases, the leading cause of mortality and morbidity in Western countries. Two inbred mouse strains, C57BL/6J and A/J, have marked differences in susceptibility to obesity, atherosclerosis, and vessel remodeling. However, it is unclear how these diverse genetic backgrounds influence pathways known to regulate thrombosis and hemostasis. The objective of this study was to evaluate thrombosis and hemostasis in these two inbred strains and determine the phenotypic response of A/J chromosomes in the C57BL/6J background.

Despite data suggesting that the adenovirus E1A protein of 243 amino acids creates an S-phase environment in quiescent cells by overcoming the nucleosomal repression of E2F-regulated genes, the precise mechanisms underlying E1A's ability in this process have not yet been defined at the biochemical level. In this study, we show by kinetic analysis that E1A, as opposed to an E1A mutant failing to bind p130, can temporally eliminate corepressor complexes consisting of p130-E2F4 and HDAC1/2-mSin3B from the promoters of E2F-regulated genes in quiescent cells. Once the complexes are removed, the di-methylation of H3K9 at these promoters becomes dramatically diminished, and this in turn allows for the acetylation of H3K9/14 and the recruitment of activating E2F family members, which is then followed by the transcriptional activity of the E2F-regulated genes. Remarkably, although an E1A mutant that can no longer bind to a histone acetyltransferase (PCAF) is as capable as wild-type E1A in eliminating corepressor complexes and methyl groups from the promoters of these genes, it cannot mediate the acetylation of H3K9/14 or induce their transcription. These findings suggest that corepressors as well as coactivators are acted upon by E1A to derepress E2F-regulated genes in quiescent cells. Thus, our results highlight for the first time a functional relationship between E1A and two transcriptional pathways of differing functions for transitioning cells out of quiescence and into S phase.Human adenoviruses normally infect quiescent or terminally differentiated cells. Central to this infectivity is the action of the small-size adenovirus E1A protein of 243 amino acid (aa) residues (243R), which creates a condition favorable for viral replication (1). As such, this protein is principally responsible for transitioning cells out of quiescence and into S phase or for reactivating DNA synthesis in terminally differentiated muscle cells (3,17,25). Earlier studies have shown that the activities of E1A in this context are largely dependent upon its ability to physically associate with members of the retinoblastoma family of proteins, e.g., pRb and p130 (6,10,17). Both of these proteins are widely known for their ability to regulate the E2F family of transcription factors (E2F1 to E2F5), which play pivotal roles in regulating the expression of genes involved in cell cycle reentry and DNA synthesis (2). In general, the functions of the E2Fs serve broad roles, with E2F1 to -3 acting as transcriptional activators and E2F4 to -5 as transcriptional repressors. The remaining E2Fs (E2F6 to -8) can also act as transcriptional repressors, but in an Rb-independent manner (29). In cycling cells, pRb is believed to inhibit the activating function of E2F1 by recruiting chromatin-modifying complexes with histone deacetylase (HDAC) or histone methyltransferase activity to E2F-regulated genes (8). However, such recruitment may be important only for repressing key E2F promoters under specific conditions (e.g., Ras-induced senescence) since chromatin imm...