Limits...
Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy.

Haery L, Thompson RC, Gilmore TD - Genes Cancer (2015)

Bottom Line: The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs).HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors.In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boston University, Boston, MA, USA.

ABSTRACT
The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas.

No MeSH data available.


Related in: MedlinePlus

The general structures of human HATs and HDACsSchematic representations are drawn approximately to scale. The catalytically active domains and other conserved domains are shown: acetyltransferase domain (KAT), bromodomain (Br), cysteine/histidine domain (CH), KIX domain, PH-D finger (PHD), helix-loop-helix domain (HLH), LXXLL motif (LX), PAS domain (PAS). All human HATs are listed with the gene alias in parentheses. Size of each HAT is shown as number of amino acids. A representative HAT (indicated by asterisk) is shown for each family. All HDACs are listed with their predominant subcellular localizations; those that shuttle between the nucleus and cytoplasm are indicated as nuc/cyt. Catalytic domains are indicated with green boxes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4482241&req=5

Figure 1: The general structures of human HATs and HDACsSchematic representations are drawn approximately to scale. The catalytically active domains and other conserved domains are shown: acetyltransferase domain (KAT), bromodomain (Br), cysteine/histidine domain (CH), KIX domain, PH-D finger (PHD), helix-loop-helix domain (HLH), LXXLL motif (LX), PAS domain (PAS). All human HATs are listed with the gene alias in parentheses. Size of each HAT is shown as number of amino acids. A representative HAT (indicated by asterisk) is shown for each family. All HDACs are listed with their predominant subcellular localizations; those that shuttle between the nucleus and cytoplasm are indicated as nuc/cyt. Catalytic domains are indicated with green boxes.

Mentions: There are 17 human HATs, which are divided into five families based primarily on the extent of sequence similarity [5] (Figure 1). Although HATs can act on a broad range of substrates in vitro, HATs are usually directed to specific targets in vivo, and thus, HAT families generally have distinct biological functions. The non-catalytic domains of HATs are responsible for dictating this substrate specificity, and HAT families generally have conserved protein-protein interaction and reader domains (e.g., bromodomains, PHD fingers), which enable them to localize to particular genomic sites and recognize specific chemical or epigenetic modifications. The size of the catalytic HAT domain and the mechanism of catalysis also differ between HAT families. For example, CBP and p300 utilize a “hit and run” kinetic model defined by an initial binding of acetyl-CoA followed by transient binding to the target lysine [6, 7], whereas the GNAT family HATs adopt a ternary complex during catalysis [8].


Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy.

Haery L, Thompson RC, Gilmore TD - Genes Cancer (2015)

The general structures of human HATs and HDACsSchematic representations are drawn approximately to scale. The catalytically active domains and other conserved domains are shown: acetyltransferase domain (KAT), bromodomain (Br), cysteine/histidine domain (CH), KIX domain, PH-D finger (PHD), helix-loop-helix domain (HLH), LXXLL motif (LX), PAS domain (PAS). All human HATs are listed with the gene alias in parentheses. Size of each HAT is shown as number of amino acids. A representative HAT (indicated by asterisk) is shown for each family. All HDACs are listed with their predominant subcellular localizations; those that shuttle between the nucleus and cytoplasm are indicated as nuc/cyt. Catalytic domains are indicated with green boxes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482241&req=5

Figure 1: The general structures of human HATs and HDACsSchematic representations are drawn approximately to scale. The catalytically active domains and other conserved domains are shown: acetyltransferase domain (KAT), bromodomain (Br), cysteine/histidine domain (CH), KIX domain, PH-D finger (PHD), helix-loop-helix domain (HLH), LXXLL motif (LX), PAS domain (PAS). All human HATs are listed with the gene alias in parentheses. Size of each HAT is shown as number of amino acids. A representative HAT (indicated by asterisk) is shown for each family. All HDACs are listed with their predominant subcellular localizations; those that shuttle between the nucleus and cytoplasm are indicated as nuc/cyt. Catalytic domains are indicated with green boxes.
Mentions: There are 17 human HATs, which are divided into five families based primarily on the extent of sequence similarity [5] (Figure 1). Although HATs can act on a broad range of substrates in vitro, HATs are usually directed to specific targets in vivo, and thus, HAT families generally have distinct biological functions. The non-catalytic domains of HATs are responsible for dictating this substrate specificity, and HAT families generally have conserved protein-protein interaction and reader domains (e.g., bromodomains, PHD fingers), which enable them to localize to particular genomic sites and recognize specific chemical or epigenetic modifications. The size of the catalytic HAT domain and the mechanism of catalysis also differ between HAT families. For example, CBP and p300 utilize a “hit and run” kinetic model defined by an initial binding of acetyl-CoA followed by transient binding to the target lysine [6, 7], whereas the GNAT family HATs adopt a ternary complex during catalysis [8].

Bottom Line: The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs).HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors.In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boston University, Boston, MA, USA.

ABSTRACT
The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas.

No MeSH data available.


Related in: MedlinePlus