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.
Smith
Christine M
CM
Division of Basic Sciences and Proteomics Facility, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Haimberger
Zara W
ZW
Johnson
Catherine O
CO
Wolf
Alex J
AJ
Gafken
Philip R
PR
Zhang
Zhongli
Z
Parthun
Mark R
MR
Gottschling
Daniel E
DE
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