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of the microRNAs is seen in daf - 12 ( rh61 ) alleles, dependent on corepressor
din - 1 / SHARP .
A simplifying model is that, in favorable environments global production
of the DAs results in activation of DAF-12 in target tissues, where it turns on
the microRNAs. They in turn downregulate HBL-1, inhibiting earlier L2
programs to allow for later L3 programs ( Abbott et al., 2005 ). DAF-12 may
also directly promote L3 programs by turning on genes that specify this tem-
poral fate. In unfavorable environments, animals enter the dauer stage, gen-
erally repress microRNA expression, and shut down the developmental
timer ( Fig. 7.1 A). Thus, DAF-12- let - 7s work as hormone-regulated switch
governing developmental progression in response to the environment.
Evidence suggests that steroid regulation of let - 7 microRNAs is a
conserved ancestral pathway. In Drosophila , 20-hydroxyecdysone and its
receptor rapidly transactivate pri- let - 7 complex and regulate larval to adult
developmental events in various tissues ( Chawla & Sokol, 2012; Wu, Chen,
Mercer, & Sokol, 2012 ). In mammals, the estrogen and vitamin-D receptors
reportedly regulate let - 7 and let - 7 -related microRNAs ( Bhat-Nakshatri
et al., 2009; Ting, Messing, Yasmin-Karim, & Lee, 2013 ). Estrogen also reg-
ulates genes involved in microRNA biogenesis ( Gupta, Caffrey, Callagy, &
Gupta, 2012 ). These observations hint that mammalian steroidal receptors
too may regulate stage transitions by influencing microRNA transcription,
biogenesis, and activity.
3.4. DAF-12 targets include heterochronic genes
let - 7 microRNAs are not the only DAF-12 targets responsible for influenc-
ing developmental timing. Identification of DAF-12 target genes by chro-
matin immunoprecipitation and transcriptome analysis reveals that DAF-12
resides at the promoters of multiple heterochronic genes including those
involved in microRNA biogenesis and activity ( alg - 2 / argonaut , nhl - 2 ),
genes involved in the L2/L3 switch ( lin - 46 / gephryin - like , lin - 28 ), and
the larval to adult transition ( lin - 41 /TRIM71, dre - 1 /FBXO11, lin - 42 /PER)
( Hochbaum et al., 2011 ). In particular, DAF-12 may have a role in down-
regulating lin - 28 expression at both the mRNA and protein level
( Hochbaum et al., 2011; Morita & Han, 2006; Seggerson, Tang, & Moss,
2002 ), although some observations contradict these results ( Hammell,
Karp, & Ambros, 2009 ). DAF-12 also affects several dauer transcription fac-
tors ( daf - 3 / Smad , daf - 16 / FOXO ), as well as its own corepressor ( din - 1 /
SHARP ). These cross-regulatory relationships suggest that DAF-12 activity
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