Dispatch R227
Dosage compensation: X-repress yourself
William B. Wood, Adrian Streit and Weiqing Li
Dosage compensation in Caenorhabditis elegans
involves the sex-specific recruitment to the X
chromosome of a protein complex, the nature of which
suggests that there are mechanistic links between
chromosome segregation and global transcriptional
regulation.
Address: Department of Molecular, Cellular and Developmental
Biology, University of Colorado, Boulder, Colorado 80309-0347, USA.
E-mail: wood@colorado.edu
Electronic identifier: 0960-9822-007-R0227
Current Biology 1997, 7:R227–R230
© Current Biology Ltd ISSN 0960-9822
Animals whose sex is determined by different combina-
tions of sex chromosomes face something of a paradox.
The embryo must be able to distinguish between two
alternative karyotypes in order to initiate the appropriate
sexual differentiation. In most such animals, however, the
differences between these karyotypes must be
compensated for to ensure that non-sex-determining
genes on the sex chromosomes are expressed at similar
levels in the two sexes. Mammals such as ourselves, with
XX female / XY male sex determination, solve this
problem by separating it into two. Sex is determined inde-
pendently of the number of X chromosomes by the pres-
ence or absence of a Y chromosome, which carries few
genes with functions other than sex determination and
male sexual differentiation. X chromosome dosage com-
pensation is accomplished by effectively shutting down
one or the other X chromosome in every cell of an early
female embryo, by a mechanism that persists through
subsequent cell generations and is irreversible in most
tissues throughout life [1].
For invertebrates, such as the fruitfly Drosophila and the
nematode Caenorhabditis elegans, in which sex is deter-
mined only by the number of X chromosomes — actually
the X:A ratio of X chromosomes to sets of autosomes —
the problem is trickier because sex must be determined
by the same karyotypic difference that dosage com-
pensation is designed to counteract. In flies, females are
XX and males XY, but the Y chromosome plays no role in
sex determination. In worms, hermaphrodites are XX
and males XO. In each of these organisms, the problem
posed above is solved by somewhat mind-boggling
pathways of interacting regulatory genes, similar in
complexity but different in mechanism, which coordi-
nately control the effectors of sex determination and
dosage compensation.
In the fly and the worm, both sex determination and
dosage compensation are under the control of a master
regulatory gene on the X chromosome which is differen-
tially activated in the two sexes according to the copy
number of several other X-linked loci, known as numera-
tor elements. Quite a lot is now known about the mecha-
nism of this initial decision in flies, less in worms [2]. But
now the logic, and some of the molecular functions, of the
worm’s regulatory apparatus, replete with branches, feed-
forward and feedback loops, have become clear, due
almost entirely to the work of Barbara Meyer and her col-
leagues, following earlier elucidation of the sex-determi-
nation pathway per se by Jonathan Hodgkin [3].
Dosage compensation in C. elegans is accomplished by
down-regulating X chromosome gene expression in XX
animals: not by inactivating one X, as in mammals, but
rather by globally repressing expression of the genes on
both X chromosomes by a factor of two relative to their
expression level in XO animals [4,5]. This chromosome-
wide modulation must be superimposed on the various
gene-specific controls that regulate X-linked genes during
development.
The model pathway for regulation of dosage compensa-
tion and its relationship to sex determination, shown in
Figure 1, is based on a series of incisive genetic analyses
by Meyer and colleagues between 1987 and 1995
(reviewed in [2]). The results suggested that xol-1 (for XO
lethal), which is activated specifically in XO animals, neg-
atively regulates each of three sdc (sex determination and
dosage compensation) genes. These in turn negatively
regulate the first gene in the sex-determination pathway,
Figure 1
Proposed pathway of regulatory gene interactions for the control of sex
determination and dosage compensation in C. elegans (some
suggested regulatory loops have been omitted). The sdc genes act to
repress her-1 expression and activate dpy genes; dpy-30 is now
thought to act further upstream in the pathway (see Fig. 2).
X:A xol-1
sdc-1 dpy-21
her-1
Transcription of
X-linked genes
Male sex
determination
sdc-2
sdc-3
dpy-26
dpy-27
dpy-28
(dpy-30)
High
Low
Yes
No
Off
On
On
Off
Off
On
On
Off
XO 0.5
XX 1.0
© 1997 Current Biology