Fig 1.
Only some of the maternally methylated imprints look like retrotransposons, but all are controlled by KRAB-ZF proteins.
(A) Table showing progress in clarifying the transposon-imprinting link. Initial studies looked at individual genes (in italics) from the approximately 100 known; later work concentrated on ICRs (in bold) that regulate multiple genes: there are approximately 19 ICRs. Although a relatively small number of imprinted genes show clear evidence of retrotransposition, almost all are bound by, and many dependent on, zygotically expressed KRAB-ZFP57 for methylation maintenance. Recently, the Trono and Ferguson-Smith labs have demonstrated a clear role for a second KRAB-ZF protein (called ZNF445) in regulating a partially overlapping set of ICRs. If maternally expressed stores of ZFP57 are also depleted, even more ICRs are affected, thus covering 18/19 ICR. The one remaining ICR is Peg10, which is clearly related itself to the sushi retrotransposon class (row 2) and may be regulated by an as-yet-undiscovered KRAB-ZF protein. (B) Schematic summarizing the data shown in (A): the 3 smallest circles refer to genes, the larger to ICR, as above. Together, these studies clearly link all imprinted loci with host defense. CG, cytosine-guanine; ICR, imprint control region; KRAB-ZF, Krüppel-associated box–zinc finger; ZFP57, zinc finger protein 57; ZFN445, zinc finger 445, ZNF445.
Fig 2.
Identical cellular machinery is used to repress retrotransposons and imprints.
From the large pool of KRAB-ZFPs known in mice, most target specific retrotransposon subfamilies, such as ZFP809 (shown at left [39]). which binds to a consensus sequence present on most PBS-pro-containing ERVs in mice, or ZNF10, which specifically targets HIV-1 in human [40]. Proteins involved in imprinting such as ZFP57 (shown at right) and ZNF445 appear to bind consensus sequences that are found at some ERVs but also at all ICRs. In both situations, the KRAB box recruits the transcriptional corepressor KAP1, which can mediate transcriptional shut-down in the short term in ES cells and early embryo through HP1 and SETDB1-mediated H3K9me3 deposition and in the longer term, postimplantation by recruiting DNMTs to methylate the DNA. DMMT, DNA methyltransferase; ERV, endogenous retrovirus; ES, embryonic stem; HIV-1, human immunodeficiency 1; HP1, Heterochromatin protein 1; IAP, intracisternal A particle; ICR, imprint control region; KAP1, KRAB-associated protein 1; KRAB-ZF, Krüppel-associated box–zinc finger; LTR, long terminal repeat; PBS-pro, primer binding site-proline; SETDB1, SET domain bifurcated 1; ZNF, zinc finger; ZFP, zinc finger protein.