Selective loss of a DNase I hypersensitive site upstream of the tyrosine aminotransferase gene in mice homozygous for lethal albino deletions.
Several overlapping chromosomal deletions spanning the albino locus in the mouse cause perinatal lethality when homozygous and a block in the transcriptional induction of various unlinked hepatocyte-specific genes. Studies of such lethal albino deletion homozygotes in perinatal stages revealed a deficiency in the transcriptional inducibility of the tyrosine aminotransferase (TAT) gene by glucocorticoids; yet, glucocorticoid receptor and hormone levels were shown to be unaffected. To identify a molecular defect underlying the failure of inducible expression, we examined the chromatin structure of the TAT gene. Whereas in wild-type animals the TAT promoter becomes DNase I hypersensitive at birth, such hypersensitivity fails to develop in lethal albino deletion homozygotes. By contrast, the deletions do not affect the appearance of three DNase I-hypersensitive sites upstream of the TAT promoter in the liver, nor do they affect two hypersensitive sites upstream of the expressed alpha-fetoprotein gene. These findings demonstrate that the abnormality of chromatin structure identified in lethal albino deletion homozygotes occurs on a highly selective basis. Specifically, normal differentiation of the TAT promoter chromatin appears to depend directly or indirectly on the action and product of a gene mapping within the deleted region.
Zaret
K S
KS
Section of Biochemistry, Brown University, Providence, RI 02912.
Milos
P
P
Lia
M
M
Bali
D
D
Gluecksohn-Waelsch
S
S
D000417:Albinism / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D003850:Deoxyribonuclease I; D015971:Gene Expression Regulation, Enzymologic; D005804:Genes, Lethal; D008099:Liver / Q000196:embryology / Q000201:enzymology; D051379:Mice; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D014444:Tyrosine Transaminase / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000235:genetics
D000509:alpha-Fetoproteins; D014444:Tyrosine Transaminase; D003850:Deoxyribonuclease I