Heritable chromatin structure: mapping "memory" in histones H3 and H4.
Telomeric position effect in Saccharomyces cerevisiae is a chromatin-mediated phenomenon in which telomere proximal genes are repressed (silenced) in a heritable, but reversible, fashion. Once a transcriptional state (active or silenced) is established, however, there is a strong tendency for that state to be propagated. Twenty-five years ago, H. Weintraub and colleagues suggested that such heritability could be mediated by posttranslational modification of chromatin [Weintraub, H., Flint, S. J., Leffak, I. M., Groudine, M. & Grainger, R. M. (1977) Cold Spring Harbor Symp. Quant. Biol. 42, 401-407]. To identify potential sites within the chromatin that might act as sources of "memory" for the heritable transmission, we performed a genetic screen to isolate mutant alleles of the histones H3 and H4 genes that would "lock" telomeric marker genes into a silenced state. We identified mutations in the NH(2)-terminal tail and core of both histones; most of the amino acid changes mapped adjacent to lysines that are known sites of acetylation or methylation. We developed a method using MS to quantify the level of acetylation at each lysine within the histone H4 NH(2)-terminal tail in these mutants. We discovered that each of these mutants had a dramatic reduction in the level of acetylation at lysine 12 within the histone H4 tail. We propose that this lysine serves as a "memory mark" for propagating the expression state of a telomeric gene: when it is unacetylated, silent chromatin will be inherited; when it is acetylated an active state will be inherited.
Division of Basic Sciences and Proteomics Facility, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Christine M
CM
Smith
Zara W
ZW
Haimberger
Catherine O
CO
Johnson
Alex J
AJ
Wolf
Philip R
PR
Gafken
Zhongli
Z
Zhang
Mark R
MR
Parthun
Daniel E
DE
Gottschling
D000107:Acetylation; D000595:Amino Acid Sequence; D002843:Chromatin / Q000737:chemistry / Q000235:genetics*; D006657:Histones / Q000737:chemistry / Q000235:genetics*; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D016615:Telomere; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D008239:Lysine