Signaling coupled epigenomic regulation of gene expression

Abstract

Inheritance of genomic information independent of the DNA sequence, the epigenetics, as well as gene transcription are profoundly shaped by serine/threonine and tyrosine signaling kinases and components of the chromatin remodeling complexes. To precisely respond to a changing external milieu, human cells efficiently translate upstream signals into post-translational modifications (PTMs) on histones and coregulators such as corepressors, coactivators, DNA-binding factors and PTM modifying enzymes. Because a protein with multiple residues for putative PTMs is expected to undergo more than one PTM in cells stimulated with growth factors, the outcome of combinational PTM codes on histones and coregulators is profoundly shaped by regulatory interplays between PTMs. The genomic functions of signaling kinases in cancer cells are manifested by the downstream effectors of cytoplasmic signaling cascades as well as translocation of the cytoplasmic signaling kinases to the nucleus. Signaling-mediated phosphorylation of histones serves as a regulatory switch for other PTMs, and connects chromatin remodeling complexes into gene transcription and gene activity. Here, we will discuss the recent advances in signaling-dependent epigenomic regulation of gene transcription using a few representative cancer-relevant serine/threonine and tyrosine kinases and their interplay with chromatin remodeling factors in cancer cells.

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

“… 45 , 49 Histones can also be phosphorylated in serine, threonine and tyrosine residues by a plethora of kinases, a selection of which is indicated in Table 1 , with diverse effects on chromatin remodelling and gene expression. 50 At this point, it is important to mention that the writing of histone PTMs can be dynamically regulated at different levels, including by extracellular signals, as initially reported for acetylation reactions 51 and later profusely analysed for phosphorylation events linked to signalling kinase cascades. 50 It is also important to emphasise that an extensive and intricate crosstalk exists between different epigenetic marks in the regulation of gene expression.…”

“… 50 At this point, it is important to mention that the writing of histone PTMs can be dynamically regulated at different levels, including by extracellular signals, as initially reported for acetylation reactions 51 and later profusely analysed for phosphorylation events linked to signalling kinase cascades. 50 It is also important to emphasise that an extensive and intricate crosstalk exists between different epigenetic marks in the regulation of gene expression. This was initially shown to occur between DNA CpG methylation and histone deacetylation, leading to chromatin condensation and gene repression.…”

“…However, the nature of the phosphatases involved in histone dephosphorylation and their regulation remains to be fully characterised. 50 From this brief overview of the machinery that establishes the epigenetic marks on chromatin one may grasp its enormous intricacy. Nevertheless, this is just one layer of complexity.…”

Sublethal β-lactam antibiotics induce PhpP phosphatase expression and StkP kinase phosphorylation in PBP-independent β-lactam antibiotic resistance ofStreptococcus pneumoniae

“…Kinases play key roles in signal transduction in both eukaryotes and prokaryotes and are activated by either phosphorylation or dephosphorylation [44]. Unlike eukaryotes, histidine kinases but not serine/threonine/tyrosine (Ser/Thr/Tyr) kinases act as the major signal sensors and transducers in prokaryotic bacteria [45].…”

Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

“…Furthermore, overexpression of activated PAK1 in mammary glands was sufficient for triggering hyperplasia and tumorigenesis [78][79][80]. Relevance of these PAK1 functions in cancer was established by demonstrating widespread PAK1 upregulation in human breast cancer and a gradual increase in PAK1 levels as a function of breast cancer grades [81][82][83][84][85]. During these studies, we also discovered nuclear PAK1 in breast cancer and its association with tamoxifen-resistant phenotypes [82][83][84][85].…”