Signaling-to-chromatin pathways in the immune system

Abstract

Complex organisms are able to respond to diverse environmental cues by rapidly inducing specific transcriptional programs comprising a few dozen genes among thousands. The highly complex environment within the nucleus-a crowded milieu containing large genomes tightly condensed with histone proteins in the form of chromatin-makes inducible transcription a challenge for the cell, akin to the proverbial needle in a haystack. The different signaling pathways and transcription factors involved in the transmission of information from the cell surface to the nucleus have been readily explored, but not so much the specific mechanisms employed by the cell to ultimately instruct the chromatin changes necessary for a fast and robust transcription activation. Signaling pathways rely on cascades of protein kinases that, in addition to activating transcription factors can also activate the chromatin template by phosphorylating histone proteins, what we refer to as "signaling-to-chromatin." These pathways appear to be selectively employed and especially critical for driving inducible transcription in macrophages and likely in diverse other immune cell populations. Here, we discuss signaling-to-chromatin pathways with potential relevance in diverse immune cell populations together with chromatin related mechanisms that help to "solve" the needle in a haystack challenge of robust chromatin activation and inducible transcription.

Keywords: chromatin; histone phosphorylation; immune responses; signaling.

FIGURE 1

Signaling-to-chromatin in the immune system. A, Western blot showing levels of histone H3 phosphorylation at residues S28 and S31 (H3.3) upon stimulation of different immune cell types with relevant stimuli for the indicated times. B, Different immune cell receptors are able to engage MAPK and NF-κB pathways to increase chromatin phosphorylation and stimulate transcription of target genes

FIGURE 2

Histone phosphorylation-mediated binary switches for inducible transcription. A, General model describing histone phosphorylation activity through ejection of corepressors (left) and stimulation of coactivators (right). B, General model of H3S28ph and H3.3S31ph ability to eject the transcriptional corepressor PRC2 and increase binding and activity of p300. C, Co-transcriptional phosphorylation of H3.3S31 by IKKα ejects ZMYND11 and stimulates the activity of SETD2. D, Common mechanism of action for H3S10ph and H3Y41ph in the ejection of HP1. E, Events linking H3S10 phosphorylation and transcription activation through the stepwise recruitment of coactivators (MOF, GCN5, BRD4, and P-TEFb) and Pol-II CTD phosphorylation. F, Kinase activity of PKCβ on H3T6 prevents demethylation of H3K4 by ejecting corepressors JARID1B and LSD1. G, Phosphorylation of H3T11 by PRK1 recruit coactivator JMJD2C to demethylate H3K9 and activate transcription