It is important to investigate how genetic variation affects different cellular phenotypes and what are the mechanistic relationships among them in order to better understand the genetic basis of disease. The objective of this thesis is to gain insights into human gene regulation in the context of natural variation of cellular traits and DNA sequence. In this thesis I present the results of two main studies in which we have examined in an integrative manner all the pair wise relationships among genetic variation, DNA methylation and gene expression to: (a) study the participation of DNA methylation in gene regulation; and (b) examine the tissue- specificity of genetic and epigenetic regulatory effects in gene expression and alternative splicing. Additionally, I present my contribution to a third study that has assessed the allelic specificity and allelic coordination across multiple regulatory layers. Overall, these studies have yielded insights into the regulatory architecture of the genome across tissues, and highlight a scenario in which the epigenome is a marker for regulatory activity that is mainly driven by sequence-specific transcription factors.