Models for regulation of TREM by Rpd3L HDAC. (A) Upon environmental changes, unnecessary genes are repressed by a stimulus (1st repression). TREM upon re-exposure to the same stimulus promotes optimal repression of unnecessary genes to save cellular resources (2nd repression). Rpd3L HDAC bound to active promoters facilitates TREM but the factors that antagonize the effect of Rpd3L need to be determined. (B) Set1 complex (Set1C) is targeted to active genes via the interaction with elongating RNA Pol II and/or nascent RNA transcripts and deposits H3K4me3 at active promoters. This methyl mark is recognized by the Pho23 PHD finger and instructs Rpd3L to deacetylate histones. Hypoacetylation by the H3K4me3-Rpd3L pathway results in optimal repression of unnecessary genes by TREM (wild type). In contrast, hyperacetylation by the loss of Rpd3L function may result in sustained expression of unnecessary ones (mutants for Rpd3L).