Dot1a-AF9 Complex Mediates Histone H3 Lys-79 Hypermethylation and Repression of ENaCα in an Aldosterone-sensitive Manner

Zhang, Wenzheng; Xia, Xuefeng; Reisenauer, Mary Rose; Hemenway, Charles S.; Kone, Bruce C.

doi:10.1074/jbc.m601903200

Cited by 152 publications

(240 citation statements)

References 37 publications

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“…Decreased methylation through loss of Af9 corresponded with increased expression of TBR1. This finding of AF9-dependent transcriptional control via H3K79me2 supports other studies, reporting the AF9-dependent regulation of transcription through H3K79 methylation (12,13). In the latter study, presence of AF9 is also coupled to an increase in H3K79me2 at the ENaCα promoter and its transcriptional repression.…”

Section: Discussionsupporting

confidence: 79%

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Büttner

Johnsen

Kügler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.A F9/MLLT3 is one of multiple fusion partners of the histone methyltransferase MLL1 in acute leukemia (1, 2). However, mutations of the AF9/MLLT3 gene alone are not associated with leukemia but are implicated in anterior homeotic transformations during mouse development (3), and in neurodevelopmental diseases, such as mental retardation, epilepsy, and ataxia in human patients (4,5). Little is known about AF9 function in the CNS, although its expression pattern implies a role during development of the forebrain and cerebellum (6). In the mouse forebrain, Af9 is transcribed in the subventricular zone (SVZ), a neurogenic compartment that harbors progenitors for upper layer neurons (7,8). Af9 is also expressed in neurons dispersed over all cortical layers and diverges in this respect from other SVZ markers, such as Svet1 and Cux2 (6). On the molecular level, AF9 mediates transcriptional activation and was classified as a proto-oncogene (9). The AF9 protein interacts with many different factors and has been implicated in different cellular processes (9-11). In the extensive network of interacting proteins, AF9 associates with DOT1L (12, 13), the main enzyme responsible for histone H3 methylation at lysine 79 (14-16). Dot1 is implicated in UV damage repair (17), and affects gene expression in yeast, flies, and mammals (18, 19), whereas histone H3 lysine 79 (H3K79) methylation correlates with gene activation (20) and suppression (21). Following this line, AF9-DOT1L complexes mediate transcriptional activation through increased levels of dimethylated H3K79 (13), but are also capable of transcriptional repression through hypermethyla...

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Section: Discussionsupporting

confidence: 79%

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Büttner

Johnsen

Kügler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…85,86 Furthermore, DOT1L is found in nuclear complexes with AF10, ENL, and other MLL translocation partners AF4 and AF9. 85,[87][88][89][90] Ectopically expressed MLL-AF10, or a synthetic, not naturally occurring MLL-DOT1 fusion, was shown to localize to the HOXA9 locus and increase K79 methylation. This corresponded to increased HOXA9 expression, consistent with the notion that H3K79 methylation is an activating chromatin modification.…”

Section: H3k79mentioning

confidence: 99%

Chromatin maps, histone modifications and leukemia

Neff

Armstrong

2009

Leukemia

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“…22,27,28 ). ChIP with anti-me2K79 detected no substantial signals in Ra and R1 regions but robust signals from R0, R2, and R3 in wild-type (WT) mice ( Figure 5B).…”

Section: Af17 Is Expressed In Aqp2-expressing Renal Collecting Duct Pmentioning

confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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Dot1a-AF9 Complex Mediates Histone H3 Lys-79 Hypermethylation and Repression of ENaCα in an Aldosterone-sensitive Manner

Cited by 152 publications

References 37 publications

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Chromatin maps, histone modifications and leukemia

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

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