Project 5 (Epigenetics) is a new, but integral part of the Texas Center for Learning Disabilities, which now moves into the field of genetics. As such is highly responsive to the RFA-HD-17-006 in that it focuses on adolescents with severe reading problems in Grades 7-8 who are English learners (Els), i.e., an understudied and underserved subpopulation of US adolescents. It has been designated a high-risk?high-reward project because it offers a novel line of research attempting to investigate the correlations between the dynamics of response to intervention (RTI) and DNA methylation across 21 months, sampling behavior, the brain, and the methylome at three time points (prior to the beginning, in the middle, and upon completion of a high-quality intensive reading intervention). Project 5 offers a set of objectives and hypotheses formulated around this opportunity (SA1). In addition to content contributions that will be generated while achieving SA1, Project 5 offers two methodological aims (SA2 and SA3) to address issues concerning the specificity and generality of the characteristics of the methylome when ascertained from different populations of cells. These issues are central to and remain unresolved in the bourgeoning field of behavioral epigenetics. To achieve its Specific Aims, Project 5 will recruit a sample of 672 adolescents stratified into three groups: typically developing students (recruited from Project 2, Attention) and Els with persistent reading difficulties (recruited from Project 3, Intervention), who are further subdivided into treated and untreated (business as usual) students. Capitalizing on the conceptualizations of learning disabilities and of RTI developed in Project 1 (Integration), Project 5 aims to investigate both categorical (group) and continuous (dimensional) indicators of reading performance and related processes cross-sectionally, as well as longitudinally at multiple levels of analyses? the epigenome, the brain, and behavior, seeking to understand individual differences in instructional response. It is hypothesized, in general, that both categorical and dimensional approaches to reading difficulties will be marked by specific characteristics of the DNA methylation profile, captured by indicators of hyper- and hypomethylation. We hypothesize that through the analyses of these characteristics, it will be possible to identify genes and gene networks that substantiate learning in general and learning to read in particular.