Prostate cancer reactivates developmental epigenomic programs during metastatic progression.

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium.

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers.

The hepatocyte nuclear factors, Hnf1a and Hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineage-determining transcription factors in the kidney proximal tubule (PT) [Martovetsky et. al., (2012) Mol Pharmacol 84:808], implying an additional level of regulation that is potentially important in developmental and/or tissue-engineering contexts.

The organic anion transporter (OAT) family: a systems biology perspective.

The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease.

Cellular and developmental strategies aimed at kidney tissue engineering.

Background: With the rate of kidney disease on the rise, and a serious imbalance between the number of patients requiring a kidney transplant and the number of available donor kidneys, it is becoming increasingly important to develop alternative strategies to restore organ function to diminish the need for human donors.

Summary: We review the current progress and future directions of a subset of these strategies which are ultimately aimed towards bioengineering a functional, implantable, kidney-like tissue construct or organoid that might be genetically matched to the patient.

Key Messages: By combining the knowledge about normal kidney development with the rapidly growing knowledge in the field of cell differentiation and transdifferentiation, there is hope that partial or complete kidney function can be restored in patients with kidney disease - including genetic disorders, acute kidney injury, or chronic kidney disease - with tissue-engineered construct(s).

Relevance of ureteric bud development and branching to tissue engineering, regeneration and repair in acute and chronic kidney disease.

Purpose Of Review: Chronic kidney disease is expected to continue to be a major health problem. There remains a huge shortage of donor tissues. A potential solution is to engineer a kidney-like tissue capable of performing differentiated renal functions.

Hepatocyte nuclear factors 4α and 1α regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters.

The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule (PT) is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors, which are thought to "sense" deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including hepatocyte nuclear factor 4α (Hnf4a) and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), peroxisome proliferator-activated receptor α (Pparα), and Tp53.

Organic anion and cation SLC22 "drug" transporter (Oat1, Oat3, and Oct1) regulation during development and maturation of the kidney proximal tubule.

Proper physiological function in the pre- and post-natal proximal tubule of the kidney depends upon the acquisition of selective permeability, apical-basolateral epithelial polarity and the expression of key transporters, including those involved in metabolite, toxin and drug handling. Particularly important are the SLC22 family of transporters, including the organic anion transporters Oat1 (originally identified as NKT) and Oat3 as well as the organic cation transporter Oct1. In ex vivo cultures of metanephric mesenchyme (MM; the embryonic progenitor tissue of the nephron) Oat function was evident before completion of nephron segmentation and corresponded with the maturation of tight junctions as measured biochemically by detergent extractability of the tight junction protein, ZO-1.