Role of chromatin states in transcriptional memory

Abstract

Establishment of cellular memory and its faithful propagation is critical for successful development of multicellular organisms. As pluripotent cells differentiate, choices in cell fate are inherited and maintained by their progeny throughout the lifetime of the organism. A major factor in this process is the epigenetic inheritance of specific transcriptional states or transcriptional memory. In this review, we discuss chromatin transitions and mechanisms by which they are inherited by subsequent generations. We also discuss illuminating cases of cellular memory in budding yeast and evaluate whether transcriptional memory in yeast is nuclear or cytoplasmically inherited.

Figure 1. Mechanisms for nuclear and cytoplasmic inheritance of transcriptional memory

A multipotent progenitor cell can respond to a particular signal(s) by altering its transcriptional profile. This step can lead to cell-fate commitment. Memory of adopted cell fate can be transmitted by various epigenetic/chromatin based mechanisms or by cytoplasmic signals. Changes in chromatin state can involve DNA-cytosine methylation, histone modifications and/or histone variants. Cytoplasmic inheritance could involve a signal-induced peptide, RNA or small molecule that maintains target genes in an ON or OFF state. Persistence of cellular memory in each case depends on faithful transmission of the ‘memory mark’ to subsequent generations. See text for details.

Figure 2. Schematic representation of activation of the GAL1-10 locus

Transcriptional activation of GAL genes requires the presence of galactose sugar. Extracellular galactose is transported to the cytoplasm by the Gal2p permease. Intracellular galactose binds the Gal3p co-inducer protein and this complex inactivates Gal80p repressor. Inactivation of Gal80p leads to activation of the Gal4p activator. Gal4p is a transcription factor that binds to DNA sites upstream of the structural genes, like GAL1 and GAL10 and promotes their transcription (wavy arrows). GAL1 encodes galactokinase that converts galactose to galactose-1-phosphate. Other enzymes of the GAL regulon (Gal7p, Gal10p, Gal5p) further act on this substrate to metabolize galactose for energy production. See text for details.

Figure 3. Schematic to summarize the two forms of transcriptional memory observed at the GAL gene cluster

Two different experimental regimens that lead to memory are shown. ‘Short-term’ and ‘long-term’ forms of memory differ in the required factors. See text for details.

Figure 4. Model for establishment of transcriptional memory through chromatin remodeling by SWI/SNF

Intracellular galactose activates the Gal4p activator, which recruits RNA Polymerase II and other components of the transcriptional machinery. This leads to transcription of GAL1, GAL7 and GAL10 genes. Transcription leads to formation of memory, which can be inhibited by ISWI complexes. Activated Gal4p also recruits SWI/SNF, which antagonizes the repressive function of ISWI complexes at these loci, thereby contributing to establishment of transcriptional memory.