SPECIAL ARTICLE www.jasn.org Epigenetics, Development, and the Kidney Gregory R. Dressler Department of Pathology, University of Michigan, Ann Arbor, Michigan ABSTRACT How cells partition the genome into active and inactive genes and how that informa- gant series of nuclear transplant experi- tion is established and propagated during embryonic development are fundamental to ments by Solter (for review see refer- maintaining the normal differentiated state. The molecular mechanisms of epigenetic ence2). Mouse zygotes containing two action and cellular memory are increasingly amenable to study primarily as a result of maternal genomes developed to midges- the rapid progress in the area of chromatin biology. Methylation of DNA and modi- tation but lacked extraembryonic tissues, fication of histones are critical epigenetic marks that establish active and silent chro- whereas zygotes with two paternal ge- matin domains. During development of the kidney, DNA-binding factors such as nomes generated mostly extraembryonic Pax2/8, which are essential for the intermediate mesoderm and the renal epithelial tissues. These classic experiments dem- lineage, could provide the locus and tissue specificity for histone methylation and onstrate the need for both maternal and chromatin remodeling and thus establish a kidney-specific fate. The role of epigenetic paternal genomes in mammalian devel- modifications in development and disease is under intense investigation and has opment. Furthermore, the early embryo already affected our view of cancer and aging. must be able to distinguish two different haploid genomes through some epige- J Am Soc Nephrol 19: 2060–2067, 2008. doi: 10.1681/ASN.2008010119 netic mechanism and subsequently erase or reprogram these epigenetic recogni- tion marks once the genomes pass Implicit in the structure of the DNA dou- WHAT IS EPIGENETICS? through the new germline. ble helix proposed by Watson and Crick More recently, the study of epigenet- was the heritable nature of the genome The term epigenetics, most broadly de- ics has concerned itself with inheritance during cell division, for one complemen- fined, refers to a type of inheritance that not just through the germline but also in tary strand served as a template to replicate is not encoded directly within the DNA somatic cells during embryonic develop- the other. Once the genetic code was re- sequences of genes. Such heritability can ment. Development can be thought of as vealed as triplets of nucleotides transcribed be through the germ line, as from parents a series of decisions that restrict the fate into messenger RNA and translated into to offspring, or from a single mother cell of rapidly dividing cells in response to proteins, the central dogma of molecular to its progeny during mitosis. In hu- positional information. Although em- biology was complete. Thus, genetics, mans, classic examples of epigenetic phe- bryonic stem cells and cells of the epiblast which predated the discovery of DNA and nomena include maternal and paternal are truly pluripotent, once gastrulation concerned itself with the abstract concepts imprinting, in which a disease phenotype occurs, the three germ layers become re- of heritability and phenotype, was explain- is differentially expressed depending on stricted in their eventual fates. Despite able in more biochemical terms as genes whether the allele is inherited from the that the cells are still proliferating rapidly were assigned to blocks of DNA sequence mother or the father. For example, dele- and do not express many differentiated and alleles became variants of such se- tions near chromosome 15q11 are asso- markers, such restriction is generally sta- quences. Despite the remarkable progress ciated with Prader-Willi syndrome, ble and inherited in all progeny cells. As made in deciphering the meaning of the when inherited from the father, yet man- cells of the neural ectoderm, mesoderm, genome, certain phenomena remained ifest a very different spectrum of pheno- outside the realm of classical genetics and types, Angelman syndrome, when inher- Published online ahead of print. Publication date the DNA centric view of inheritance. These ited through the mother. These types of available at www.jasn.org. epigenetic phenomena have received epigenetic imprinting effects likely arose Correspondence: Dr. Gregory R. Dressler, Depart- much attention in recent years because with the evolution of placental mam- ment of Pathology, 2049 BSRB 2200, University of they have a direct impact on our under- mals1 and underscore a fundamental dif- Michigan, Ann Arbor, MI 48109. Phone: 734-764- 6490; Fax: 734-763-6640; E-mail: dressler@umich. standing of genome regulation, the differ- ference between maternal and paternal edu entiated state, and the stability of cellular genomes. That haploid genomes are not Copyright ᮊ 2008 by the American Society of identity in many biologic systems. equivalent was also addressed in an ele- Nephrology 2060 ISSN : 1046-6673/1911-2060 J Am Soc Nephrol 19: 2060–2067, 2008 www.jasn.org SPECIAL ARTICLE and endoderm continue their differenti- Beads-on-a-string CH CH CH CH ation, cell fates become increasingly 3 3 CH 3 3 more restricted. The stability of the ter- 3 11 nm minally differentiated genome is best il- Ac Ac lustrated by the difficulty of cloning by Solenoid somatic cell nuclear transfer. When a nu- cleus from a specialized adult cell type is 30 nm introduced into the denucleated zygote, the epigenetic marks accumulated within that differentiated nucleus are not easily Fiber erased. Although Dolly the sheep3 first ~500 nm proved that epigenetic marks can be erased and the somatic genome repro- grammed within the cytoplasmic envi- Mitotic chromosome ronment of a fertilized egg, it is a rare and inefficient process. The loss of pluripotency and the her- itability of a differentiated state imply the genome is modified to remember pat- Figure 1. The dynamic structure of chromatin. The basic unit of chromatin is the terns of gene expression in all progeny nucleosome, a histone octamer represented by the tan-colored balls on the 11-nm string. The DNA helix is wrapped around the nucleosome, and a spacer region, bound cells. Dosage compensation by inactiva- with histone H1 or H5, separates adjacent nucleosomes. The histone tails extend out of tion of the X chromosome in female cells the nucleosome and can be modified by methylation or acetylation. The beads-on-a- is a well-studied example of a mitotically string can condense into a solenoid, a theoretical structure thought to be approximately inherited epigenetic phenomenon that 30 nm in diameter. Increased condensation leads to a chromatin fiber that is several controls gene expression patterns.4 Strik- hundred nm in diameter. The mitotic chromosomes is the most compact form of ingly, inactivation of the X chromosome chromatin in the cell. Chromatin remodeling refers to the sliding of nucleosomes along is coincident with the loss of pluripo- the string, the compaction of nucleosomes into higher order structures, and the unfold- tency as the mammalian epiblast under- ing of higher order structures into accessible chromatin. goes gastrulation. Although the initial decision to inactivate the maternal or pa- chemistry and structure, these questions consists of approximately 147 bp of the ternal X seems to be random, once the and more are now being addressed in a DNA helix wrapped around a histone oc- decision is made, all daughter cells from variety of experimental systems. tamer containing two copies of histone a single founder will have the same X H2A, H2B, H3, and H4 (Figure 1). Indi- chromosome inactivated. The inactive X vidual nucleosomes are separated by a chromosome is tightly packaged and eas- BIOCHEMISTRY OF EPIGENETICS spacer, or linker, region that are bound ily identifiable as a Barr body, yet in sub- by histone H1 or H5. The primary struc- sequent rounds of mitosis, it must be un- The study of epigenetic phenomenon has ture of chromatin is often referred to as packaged, replicated, and repackaged presupposed that genes can be marked “beads on a string” because of the ap- once again, suggesting that the silent X is somehow by modifications that are inde- pearance of the nucleosome and spacer marked through an epigenetic mecha- pendent of the primary nucleotide cod- sequences under the electron micro- nisms that distinguishes it from its active ing sequence. Such marks include the co- scope; however, this relatively unfolded counterpart. valent modification of DNA nucleotides form of chromatin can assume higher or- Because the pattern of gene expres- directly, specifically the methylation of der structures to compact the genome sion defines the differentiated state, the cysteine in CpG di-nucleotides. Modifi- even further (Figure 1). The folding and heritability of such patterns must be well cations are also found in the proteins unfolding of chromatin is a dynamic and regulated. On the autosomes, active and tightly associated with DNA. Eukaryotic regulated process that is necessary for inactive genes are present, sometimes in chromatin consists of the double- DNA replication but can also have a di- close proximity, and must be recognized stranded DNA helix and associated pro- rect impact on the accessibility of genes by positive and negative transacting fac- teins. Histones are small, highly basic to transcription machinery. tors. Does the complement of regulatory proteins that are tightly bound to the The methylation of DNA at CpG di- proteins define the