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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