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Figure 2 | Biology Direct

Figure 2

From: LINEs of evidence: noncanonical DNA replication as an epigenetic determinant

Figure 2

A hypothetical model of two modes of replication of full-length L1s as anepigenetic switch. A: Undifferentiated (early embryonic and cancer)cells. A subset of small L1-rich domains of the genome (EtoL domains as perHiratani and co-authors [45]) replicates DNA in early S (red arrow). Transcriptional competenceis imposed on these domains during early S phase of DNA replication. TheseL1-rich EtoL domains do not tether to the nuclear lamina and have a looseconformation of chromatin loops. Genes residing in these domains are linked toundifferentiated states of a cell. Noncanonical replication of FL-L1s residingin these domains might prevent them from binding to the nuclear matrix and fromrecruiting the ORCs (panel A, right) and, therefore, from being silencedthrough the ORC/HP1-mediated pathway of heterochromatin assembly. B:Differentiated and differentiating cells. Global programmed downregulation ofFL-L1s upon differentiation of pluripotent embryonic cells results in switching“off” the noncanonical mechanism of L1 DNA replication. In theabsence of L1 RNA paired with a complementary “parental” L1 DNA fornoncanonical L1 DNA replication, L1s might attach to the nuclear matrix andform intrastrand G4 structures. The majority of replication origins areassociated with G4s [80]. The L1-bound ORC might bind HP1 in a distinct chromatin environmentand, thereby, play a crucial role in the establishment of a silent state on theL1-rich/gene-rich EtoL domains (panel B, right). These domains switch to theirdefault state characterized by late replication, dense conformation, andtethering to the nuclear periphery [50] (blue arrow). Basically, the same switch from noncanonical tocanonical replication of L1s residing within EtoL domains might occur upondifferentiation of poorly differentiated cancer cells caused by the knockdownof the expression of L1s.

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