Cell type-specific regulation of a replication origin residing within an AT-rich/LINE-1-rich isochore

Differential activity of DNA replication origins located on the human chromosome band 9p22

“…RESULTS AND DISCUSSIONS Figure 1c shows that, as compared to the cells of line CH, DNA replication initiation in the HEK 293 cells occurred additionally at the point AT2, which was used previously as a control one [11,21]. At the same time, initiation near ori 1 decreased sharply in the HEK 293 cells (approximately by five times).…”

“…At the same time, local changes of chromatin, taking place within the limits of one zone of DNA replication initiation (at a distance of some kbp), easily change the activity of ori sites [14]. These data, suggesting a hierarchy at both the levels of organization of chromatin and regulation of its activity, could explain the greater epigenetic plas ticity of some components (for example, oris [11,14]) rather than a complete, i.e., extended unit such as an RD. The higher but less plastic level of chromatin organization seems to have a biological function.…”

“…Currently, if we consider different types of RDs, it is unclear what is the mechanism that directs or does not direct simultaneous change the S phase time of replication of oris and their activity during embryo genesis. Those oris that serve unregulated chromatin belong to constituent elements, while the oris that serve regulated chromatin belong to regulated (tissue specific) elements [11,17]. The first group of oris starts acting when transcription is launched in the embryo genesis and does not undergo further changes [17].…”

“…The concept of regulated/unregulated genome units was supplemented with data according to which regulated chromatin segments can be characterized not only by changes in the expression of genes and the time of their replication in S phase, but changes in activity of DNA replication initiation sites known as origins (oris) as well [10,11]. Meanwhile, changes of the time of replication of chromosome segments do not always occur together with changes of ori(s) activ ity [12,13] and vice versa.…”

“…The activity of regulated ori sites starts at differ ent stages of embryogenesis, as the genetic/epigenetic program is realized [10,19]. Detail data on the tissue specific activity of such oris were obtained only from the human β globin locus [20] and the IFNA2 locus containing human interferon alpha 2 gene [11]. In the latter work, we described one of the ori sites (the most active one, it is marked as ori 1) as differing in activity by two orders of magnitude in three lines of human cells that originated from the lung epithelium (A 549), T lymphoblasts (Jurkat) and the immortalized embry onal fibroblasts (CH).…”