Yh. Fan et al., Individual somatic H1 subtypes are dispensable for mouse development even in mice lacking the H1 degrees replacement subtype, MOL CELL B, 21(23), 2001, pp. 7933-7943
H1 linker histones are involved in facilitating the folding of chromatin in
to a 30-nm fiber. Mice contain eight H1 subtypes that differ in amino acid
sequence and expression during development. Previous work showed that mice
lacking H1(0), the most divergent subtype, develop normally. Examination of
chromatin in H0-/- mice showed that other H1s, especially H1c, H1d, and H1
e, compensate for the loss of H1(0) to maintain a normal H1-to-nucleosome s
toichiometry, even in tissues that normally contain abundant amounts of H1(
0) (A. M. Sirotkin et al., Proc. NatL. Acad. Sci. USA 92:6434-6438, 1995).
To further investigate the in vivo role of individual mammalian H1s in deve
lopment, we generated mice lacking H1c, H1d, or H1e by homologous recombina
tion in mouse embryonic stem cells. Mice lacking any one of these H1 subtyp
es grew and reproduced normally and did not exhibit any obvious phenotype.
To determine whether one of these H1s, in particular, was responsible for t
he compensation present in H1(0-/-) mice, each of the three H1 knockout mou
se lines was bred with H1(0) knockout mice to generate H1c/H1(0), H1d/H1(0)
, or H1e/H1(0) double-knockout mice. Each of these doubly H1-deficient mice
also was fertile and exhibited no anatomic or histological abnormalities.
Chromatin from the three double-knockout strains showed no significant chan
ge in the ratio of total H1 to nucleosomes. These results suggest that any
individual H1 subtype is dispensable for mouse development and that loss of
even two subtypes is tolerated if a normal H1-to-nucleosome stoichiometry
is maintained. Multiple compound H1 knockouts will probably be needed to di
srupt the compensation within this multigene family.