Epigenetics and Human Disease

Abstract

Genetic causes for human disorders are being discovered at an unprecedented pace. A growing subclass of disease-causing mutations involves changes in the epigenome or in the abundance and activity of proteins that regulate chromatin structure. This article focuses on research that has uncovered human diseases that stem from such epigenetic deregulation. Disease may be caused by direct changes in epigenetic marks, such as DNA methylation, commonly found to affect imprinted gene regulation. Also described are disease-causing genetic mutations in epigenetic modifiers that either affect chromatin in trans or have a cis effect in altering chromatin configuration.

Figure 1.

Genetic and epigenetic mechanisms underlying chromatin-related disorders.

Figure 2.

Consequences of uniparental disomy (UPD). In maternal UPD, transcripts expressed from the maternally inherited alleles are doubled, whereas those that are on the paternal alleles are lost. The opposite occurs in paternal UPD.

Figure 3.

The genetics and epigenetics of Prader–Willi syndrome (PWS) and Angelman syndrome (AS). (A) PWS and AS can be caused by genetic, epigenetic, or mixed defects. (B) The imprinted gene clusters associated with PWS and AS, indicating genes that are normally maternally or paternally expressed. The bipartite regulatory imprinted control (IC) region is indicated, showing the region critical for imprinted AS cluster control (green) and PWS gene cluster control (purple).

Figure 4.

Images of a Prader–Willi syndrome patient (A) and Angelman syndrome patient (B) illustrate the dramatic differences in the clinical features of the disorders resulting from defects in an imprinted region. (Images kindly provided by Dr. Daniel J. Driscoll and Dr. Carlos A. Bacino, respectively.)

Figure 5.

Imprinted clusters associated with the human Beckwith–Wiedemann and pseudohypoparathyroidism imprinting disorders. (A) The expression of imprinted genes at adjacent KCNQ1 and IGF2 imprinting clusters associated with BWS is displayed. Expression patterns from both parental chromosomes in control individuals are indicated. ICRs are indicated in green, which when imprinted, are shown to be DNA methylated (pink hexagon). ICR2 and the antisense KCNQ1OT1 lie within the KCNQ1 locus. The gray arrow connecting ICR1 and ICR2 indicates some kind of regulatory interaction that has been postulated. E, enhancer. (B) The 5′ region of the GNAS1 locus is illustrated, a gene implicated in PHP, indicating the parental expression in certain tissues of the different transcripts produced from alternative 5′ exons (NESP55, XL, and 1A). The reverse arrow indicates a NESP55 antisense transcript.

Figure 6.

Genetic disorders affecting chromatin in cis. (A) This photo of a Rett syndrome patient illustrates the unusual stereotyped hand movements, teeth grinding, and abnormal posture. (Photo kindly provided by Dr. Daniel G. Glaze.) (B) Micrograph of chromosomes from an immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome patient. (Courtesy of Drs. Timothy H. Bestor, Robert A. Rollins, and Deborah Bourc’his.)

Figure 7.

An example of a genetic disorder affecting chromatin in trans. The photograph is of a patient with fragile-X syndrome who, in addition to mental retardation, has the typical features of prominent forehead and large ears. (Photograph kindly provided by Dr. Stephen T. Warren.)

Figure 8.

Human diseases showing genetic alterations in regions with triplet repeats, in the form of repeat expansion or contraction, with consequential in cis chromatin structural changes. (A) The 5′ region of the FMR1 gene is shown with the CGG triplet repeat (blue shading) in normal and fragile-X-affected individuals. The chromatin-associated features of the 5′ FMR1 region are indicated in each case. The normal repeat number range (5–50) typically shows active chromatin features, whereas fully expanded repeat alleles (more than 200) have heterochromatic features. (B) The 4q35 region associated with normal and facioscapulohumeral dystrophy individuals (FSHD1) is depicted. In the normal repeat number range (11–150 units), heterochromatinization is presumed to initiate from the D4Z4 repeats (blue triangles) and spread throughout the 4q35 region (chromatin marks not shown throughout), silencing all genes. The 4q35 region in FSHD1 individuals has a contracted number of D4Z4 repeats, which is permissive to transcription of the DBE-T lncRNA (indicated in red), recruiting ASH1L and associated factors to remodel, generating euchromatin and allowing gene expression from 4q35 genes with myopathic potential. PRC2, Polycomb repressive complex 2; DRC, D4Z4-repressing complex; HP1, heterochromatin protein 1; ASH1L, absent small and homeotic disks protein 1; DBE-T, D4Z4-binding element transcript.

Figure 9.

The epigenotype plays a critical role, along with the genotype and environmental factors, in determining phenotypes.