In the setting of genomic complexity and co-regulation, it would be optimal to manipulate the entire locus simultaneously using a simple approach. Traditional methods to modulate ncRNAs typically focus on individual RNA transcripts, achieved through exogenous delivery of synthetic antisense oligonucleotides or small interfering RNAs for downregulation, or with miRNA mimics and gene delivery vectors for overexpression. These methods can be used to manipulate the entire locus simultaneously, but are limited by the potential toxicity of delivering multiple molecules at the same time and by the risk that overexpression or downregulation might not accurately mirror the natural physiological levels of non-coding transcripts. To address these limitations, we developed an innovative approach to target the regulatory regions of ncRNAs (such as promoters and enhancers). This tool leverages CRISPR activation technology, using a deactivated Cas9 (dCas9) and a single guide RNA. By exploring the functional annotation of complex loci, we have found that these genomic regions feature multiple transcriptional start sites and promoters. We observed that targeting the upstream transcriptional start sites effectively drives the transcription of multiple transcripts of different biotypes (such as lncRNA isoforms and pri-miRNAs) located near the 5′ end or up to 20 kb downstream extending to the main promoter at the 3′ end of the locus. This system offers several advantages. First, this approach activates natural regulatory elements, maintains the native expression patterns of individual transcripts and decreases the chances of inducing artefacts. Second, given that the full-length annotation of complex transcripts (such as lncRNAs) remains largely incomplete, activation of transcription through this tool can help to identify alternative splicing of isoforms or even unknown isoforms, which eliminates the need to know the exact sequence, given that reported sequences constantly evolve with improved genome annotation. Third, this strategy also facilitates the functional analysis of individual regulatory elements involved in gene regulation. Finally, the repression of complex loci can also be achieved by inhibition of regulatory regions. We have successfully modulated two complex genetic loci that have key roles in maintaining vascular homeostasis. These applications highlight the versatility of this system across various experimental contexts, including in vitro studies with delivery plasmids and in vivo research using viral vectors. As all the necessary components can be included in one vector, this approach shows promise for stem cell-based precision medicine. Taken together, this system offers a simple, combinatorial method for activating complex loci that has great translational potential.