Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice

Xiao, Zhou; Chen, Lihe; Zhou, Qiaoling; Zhang, Wenzheng

doi:10.1016/j.yexcr.2015.09.014

Cited by 19 publications

(15 citation statements)

References 49 publications

(72 reference statements)

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“…Hes1 might repress IC genes in PC cells by enhancing chromatin modification enzymes since the inactivation of histone methyltransferase Dot1l appeared to convert PCs into ICs (Xiao et al, 2016). In sum, Notch signaling might antagonize Tfcp2l1 in PC cells where Notch activates Hes1 .…”

Section: Discussionmentioning

confidence: 99%

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

Werth

Schmidt‐Ott

Leete

et al. 2017

eLife

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Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments.DOI: http://dx.doi.org/10.7554/eLife.24265.001

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Section: Discussionmentioning

confidence: 99%

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

Werth

Schmidt‐Ott

Leete

et al. 2017

eLife

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“…For example, lithium treatment [54] results in increased number of intercalated cells along with a decrease in principal cell number which may be due to principal cell trans-differentiation into intercalated cells. More recently the inactivation of dot1l , a histone H3-K79-methyltransferase, in Aqp2 -expressing cells resulted in increased intercalated cell numbers and reduced principal cells numbers [55]. In other instances such as culturing isolated intercalated cells or during the recovery after cessation of lithium treatment the intercalated cells possibly convert into principal cells [56, 57].…”

Section: Discussionmentioning

confidence: 99%

Elf5 is a principal cell lineage specific transcription factor in the kidney that contributes to Aqp 2 and Avpr 2 gene expression

Grassmeyer¹,

Mukherjee²,

deRiso³

et al. 2017

Developmental Biology

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The mammalian kidney collecting ducts are critical for water, electrolyte and acid-base homeostasis and develop as a branched network of tubular structures composed of principal cells intermingled with intercalated cells. The intermingled nature of the different collecting duct cell types has made it challenging to identify unique and critical factors that mark and/or regulate the development of the different collecting duct cell lineages. Here we report that the canonical Notch signaling pathway components, RBPJ and Presinilin1 and 2, are involved in patterning the mouse collecting duct cell fates by maintaining a balance between principal cell and intercalated cell fates. The relatively reduced number of principal cells in Notch-signaling-deficient kidneys offered a unique genetic leverage to identify critical principal cell-enriched factors by transcriptional profiling. Elf5, which codes for an ETS transcription factor, is one such gene that is down-regulated in kidneys with Notch-signaling-deficient collecting ducts. Additionally, Elf5 is among the earliest genes up regulated by ectopic expression of activated Notch1 in the developing collecting ducts. In the kidney, Elf5 is first expressed early within developing collecting ducts and remains on in mature principal cells. Lineage tracing of Elf5-expressing cells revealed that they are committed to the principal cell lineage by as early as E16.5. Over-expression of ETS Class IIa transcription factors, including Elf5, Elf3 and Ehf, increase the transcriptional activity of the proximal promoters of Aqp2 and Avpr2 in cultured ureteric duct cell lines. Conditional inactivation of Elf5 in the developing collecting ducts results in a small but significant reduction in the expression levels of Aqp2 and Avpr2 genes. We have identified Elf5 as an early maker of the principal cell lineage that contributes to the expression of principal cell specific genes.

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“…H3K79me2 generally correlates with transcriptional activity 12,14,20,50,[52][53][54][55] . However, repressive functions of DOT1L have been proposed as well [56][57][58][59] . Comparing H3K79me2 ChIP values in WT cells with the gene expression changes caused by loss of DOT1L revealed that the genes upregulated in Dot1L-KO B cells were mostly hypomethylated in WT cells, indicating that they are likely indirectly affected by the loss of DOT1L ( Fig.…”

Section: Dot1l-mediated H3k79 Methylation Is Associated With Gene Actmentioning

confidence: 99%

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation

Aslam

Alemdehy

Kwesi-Maliepaard

et al. 2019

Preprint

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Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B cell fate remain unclear. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Murine B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells showed aberrant differentiation and prematurely acquired plasma cell features. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L supports the repression of an anti-proliferative, plasma cell differentiation program by maintaining expression of the H3K27 methyltransferase Ezh2, the catalytic component of Polycomb Repressor Complex 2 (PRC2). Our findings show that DOT1L is a central modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B cell naivety and GC B cell differentiation.

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Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice

Cited by 19 publications

References 49 publications

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

Elf5 is a principal cell lineage specific transcription factor in the kidney that contributes to Aqp 2 and Avpr 2 gene expression

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation

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