Transcript Régulation de SRY - Département de biologie

3 mécanismes différents pour
déterminer le sexe
Développement mâle et femelle
Expression de la protéine SRY
La séquence de SRY
Régulation de SRY
Meiotic arrest and RA
Spermatogenèse murine
TRD Chromosome 17
TRD
Distorters et Responder des tmutants
TRD
Smok Kinase et TRD
Tortoiseshell cat/ Ecaille de tortue
Clonal selection
•
Schematic representation of XCI in female
somatic cells. In normal conditions, the ratio
of the two cell types (carrying the active and
the inactive X chromosomes) is
approximately 50:50, but in females with Xlinked dominant disorders this ratio can be
different because of a disadvantage for cells
expressing a mutant X-linked allele.
Divergence from the 50:50 ratio, known as
skewing of XCI, can be different in various
tissues and in different developmental
stages, and can vary among individuals,
causing a variable severity of the phenotype
observed. For disorders such as MLS,
OFCD, ODPD and IP, affected females
usually have totally skewed patterns of XCI,
in favour of an active wild type X
chromosome. Cell selection usually affects
only those cell lines in which the disease
gene is expressed [43]..
Activité des chromosomes X
pendant le développement
Conservation du gène Xist
X inactivation centre
Xist inactivation complèxe
Etapes moléculaires pendant
l’inactivation du chromosome X
Modifications des histones du gène
Xist
L’activité des gènes Xist pendant le
développement embryonnaire
Histone Code
Counting chromosomes
Mâle ou femelle chez la
drosophile?
Sxl et les 2 promteurs p et m
Sxl expression chez le mâle et la
femelle
La structure du gène sxl
L’épissage de sxl
Contrôle de l’épissage par tra et
msl-2
Transfert des pronoyau
Disomy et développement
Imprinting Models
Igf2-H19 locus
•
(A) A diagram illustrating CTCF-dependent
regulation of the Igf2–H19 locus, including the
differentially methylated regions, DMR1 and
DMR2, of Igf2 and the germline differentially
methylated domain (DMD) at H19. Filled and
open lollipops represent methylated and
unmethylated differentially methylated regions,
respectively. On the unmethylated maternal
allele, binding of CTCF (purple oval) blocks the
access of the Igf2 promoter to the enhancers
(small circles), which consequently can only
activate the H19 promoter. On the paternal allele,
the methylated H19 DMD does not bind CTCF,
allowing expression of Igf2. (B) A general model
of the maternal Igf2–H19 region, showing an
example of a higher-order chromatin structure
where CTCF binds at one or more sites but can
protect against methylation elsewhere. This
structure may be associated with the nuclear
matrix and involve proteins in addition to CTCF.
Tissue-specific variation in higher-order structure
could be due to different CTCF-dependent cis
elements forming the base of the loop or different
proteins acting in trans.
Imprinted Genes
•
Genomic organization of two imprinted
clusters. (a) The Igf2/H19 locus. The
maternally inherited H19 gene expresses an
untranslated RNA of unknown function when
the nearby imprinting center (IC) is
unmethylated, in which context, Igf2 is
repressed. On the paternally derived allele,
the IC is methylated (asterisks) and this
represses H19, but enables Igf2 expression.
(b) The UBE3A/UBE3A-ATS locus. The
maternally derived alleles of the UBE3A and
ATP10C genes are expressed, but the
UBE3A antisense (UBE3A-ATS),
SNURF/SNRPN, MKRN3, NDN and
MAGEL2 genes are silent and the IC just
upstream of the SNRPN promoter is
methylated (asterisks). When paternally
inherited, the upstream MKRN3, NDN and
MAGEL2 genes are expressed, as is the long
noncoding antisense RNA, UBE3A-ATS. The
UBE3A and ATP10C genes are repressed.
The c15orf2 gene, which lies inside this
imprinted cluster, is not subject to imprinting.
Igf2r/Air
•
Imprinting mechanisms across the Igf2r/Air
locus. (a) The maternal allele. The Igf2r,
Slc22a1 and Slc22a3 genes are all
expressed only from the maternally inherited
allele (orange boxes). Air is silent and the
imprint control region (Region 2, red box)
adjacent to the Air promoter is methylated
(asterisk). Genes not subject to imprinting
are shown as blue boxes. (b,c) The paternal
allele. (b) In a one-step model, Air RNA (red
line) associates with repressor proteins
(purple ovals) to form silencing complexes
that associate with sequences within or
around genes subject to imprinting (orange
boxes). In the case of Igf2r, promoter
methylation (asterisks) could be a
consequence of its silent status. (c) In a twostep model, Air transcription and/or Air RNA
induces Igf2r promoter methylation
(asterisks). The Igf2r silencing induced by
this promoter methylation then spreads
(dashed grey line and arrows) to other
genes (orange boxes) in some tissues and
at certain developmental stages
Prader-Willi
•
Molecular classes of Prader–Willi and
Angelman syndrome. Each genetic event is
parental-specific in PWS and AS. Deletions
and imprinting mutations occur with equal
frequency in both syndromes, whereas UPD
is more common in PWS than AS because
of higher rates of maternal nondysjunction.
The gene mutation class in AS appears to
be lacking in PWS, which probably indicates
that PWS represents a contiguous gene
syndrome. Abbreviations: hatched
chromosome, non-chromosome 15 in rare
balanced translocations; M, maternal (red);
M(P), maternal inheritance of imprinting
center (IC) mutations with a fixed paternal
epigenotype (horizontal lines); P, paternal
(blue); P(M), paternal inheritance of IC
mutations with a fixed maternal epigenotype;
UPD, uniparental disomy.
Angelman Prader Willi
Establishing Imprints
• Parental imprints are
established during oogenesis,
or spermatogenesis, at
sequence elements that
control the imprinted
expression (the ‘imprinting
control regions’ [ICRs]). After
fertilisation of the egg by the
sperm, these imprints are
maintained throughout
development. DNA methylation
(lollypops) is the most
consistent hallmark of imprints.
Two examples of ICRs are
depicted: an ICR with
paternally-derived (ICR1), and
one with maternally-derived
DNA methylation (ICR2).
Igf2-H19
•
The establishment and maintenance of DNA
methylation at the ICR of the Igf2–H19
locus. This ICR acquires methylation
(lollypops) during late spermatogenesis. In
the female germ line, by contrast, the ICR is
protected against methylation by the zincfinger protein CTCF. After fertilisation, and
throughout development, the maternal allele
(M, pink) continues to be protected against
methylation by CTCF binding. CTCF binding
onto the maternal chromosome creates a
chromatin boundary that prevents interaction
between the Igf2 gene and enhancers
(ovals) located downstream of H19. The
methylation on the paternal allele (P, blue) is
maintained throughout development and
prevents CTCF binding. On the paternal
chromosome, the Igf2 promoters can
therefore interact with the enhancers, but
here the H19 gene is repressed because of
the ICR methylation spreading into the
nearby H19 promoter.
DNA methylation/ICR
•
Sequence elements are important
for the sex-specific establishment
of DNA methylation at ICRs. (a) At
the ICR controlling the mouse
Rasgrf1 locus, the male-specific
establishment of methylation
requires the presence of
neighbouring repeat sequences
(open arrows). (b) The ICR at the
SNRPN gene regulates imprinting
along a large chromosomal
domain, which is deregulated in
the Prader–Willi syndrome (PWS).
For the acquisition of methylation
at the ICR in the female germ line,
a region located >30 kb further
upstream (the AS region) is
essential.
ICRs
• At the ICRs controlling (a) the Igf2r and
(b) the Kcnq1 domains, non-coding
RNAs are produced from the
unmethylated paternal allele. These
non-coding RNAs (Air at Igf2r, and Lit1
at Kcnq1) could be involved in the
paternal repression along these
domains, which extends furthest in the
placenta at both the domains. This
developmentally-regulated silencing
mechanism bears similarities with (c)
imprinted X-chromosome inactivation
in the mouse placenta, which is
brought about by ‘coating’ of the
paternal X-chromosome by the noncoding Xist transcript, and subsequent
recruitment of chromatin-modifying
complexes.
Imprinting Basics