BET Proteins Regulate Expression of Osr1 in Early Kidney Development.

Janina Schreiber,Nastassia Liaukouskaya,Lars Fuhrmann,Alexander-Thomas Hauser,Tobias B Huber,Nicola Wanner,Manfred Jung

doi:10.3390/biomedicines9121878

Janina Schreiber, Nastassia Liaukouskaya + Show 5 more

Open Access

https://doi.org/10.3390/biomedicines9121878

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Abstract

In utero renal development is subject to maternal metabolic and environmental influences affecting long-term renal function and the risk of developing chronic kidney failure and cardiovascular disease. Epigenetic processes have been implicated in the orchestration of renal development and prenatal programming of nephron number. However, the role of many epigenetic modifiers for kidney development is still unclear. Bromodomain and extra-terminal domain (BET) proteins act as histone acetylation reader molecules and promote gene transcription. BET family members Brd2, Brd3 and Brd4 are expressed in the nephrogenic zone during kidney development. Here, the effect of the BET inhibitor JQ1 on renal development is evaluated. Inhibition of BET proteins via JQ1 leads to reduced growth of metanephric kidney cultures, loss of the nephron progenitor cell population, and premature and disturbed nephron differentiation. Gene expression of key nephron progenitor transcription factor Osr1 is downregulated after 24 h BET inhibition, while Lhx1 and Pax8 expression is increased. Mining of BRD4 ChIP-seq and gene expression data identify Osr1 as a key factor regulated by BRD4-controlled gene activation. Inhibition of BRD4 by BET inhibitor JQ1 leads to downregulation of Osr1, thereby causing a disturbance in the balance of nephron progenitor cell self-renewal and premature differentiation of the nephron, which ultimately leads to kidney hypoplasia and disturbed nephron development. This raises questions about the potential teratogenic effects of BET inhibitors for embryonic development. In summary, our work highlights the role of BET proteins for prenatal programming of nephrogenesis and identifies Osr1 as a potential target of BET proteins.

Highlights

The effect of environmental influences on nephron number and consequent metabolic and epigenetic programming of nephron development has become increasingly more important in recent decades
Expression of Brd3 and Brd4 in the kidney was high at the developmental stages embryonic day 14.5 (E14.5), E16.5 and postnatal day 0 (P0), but was downregulated at 8 weeks
In situ hybridization showed enrichment of Brd2, Brd3 and Brd4 at the nephrogenic zone at P0 (Figure 1C). These results are supported by single cell sequencing data from human fetal kidneys, showing the highest expression of BRD3 in a nephron progenitor cell (NPC) subset, the pretubular aggregates (PTA) and developing nephron structures, while the highest expression of BRD2 and BRD4 was in the s-shaped bodies, distal tubules/loop of Henle, ureteric bud/collecting duct cells, PTAs and nephron progenitor cells (NPCs) (Supplementary Figure S1)

Summary

Introduction

The effect of environmental influences on nephron number and consequent metabolic and epigenetic programming of nephron development has become increasingly more important in recent decades. Nephron number has been shown to influence long-term kidney function [1]. A low nephron endowment has been linked to an increased risk of developing arterial hypertension as well as chronic kidney failure [2]. Human nephron development is complete by the time of birth and no further nephron formation occurs postnatally [3]. Factors influencing nephron number are prematurity, intrauterine growth arrest, and low or high birth weight [4,5,6]. Maternal malnutrition (especially vitamin A, vitamin D, zinc, and protein deficiencies) or maternal overnutrition (obesity, hyperglycemia in poorly controlled diabetes mellitus) correlate with a lower number of nephrons in

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