An in vitro method of high-throughput screening for one or more putative gene regulatory elements in a genome that modulate a phenotype, the method comprising: a) contacting a plurality of modified target cells with a library of single guide RNAs (sgRNAs) that target one or more gene regulatory elements within the genome, thereby generating a plurality of test cells, wherein the one or more gene regulatory elements comprise DNAse I hypersensitivity sites, Transposase-Accessible Chromatin sites, DNA methylation, epigenetic markers, or a combination thereof, and wherein the modified target cell comprises an intracellular or cell-surface marker labelled with a fluorescently-labelled specific binding protein or at least one target gene comprising a reporter gene inserted within the coding region of the target gene; b) isolating a population of test cells having a modulated phenotype by fluorescence-activated cell sorting or magnetic-activated cell sorting, wherein the modulated phenotype is a change in gene expression of the fluorescently-labelled specific binding protein or the reporter gene, and wherein the gene regulatory element modulates the gene expression of the at least one target gene or the intracellular marker or the cell-surface marker; c) quantitating the frequency of the sgRNAs within the population of isolated cells, wherein the sgRNAs that target one or more gene regulatory elements that modulate the phenotype are overrepresented or underrepresented in the isolated cells; and d) identifying and characterizing the sgRNAs within the population of isolated test cells thereby identifying the one or more gene regulatory elements that modulate the phenotype, wherein the modified target cell comprises a fusion protein, the fusion protein comprising a dCas9 domain and a p300 transcriptional activator domain. a) contacting a plurality of modified target cells with a library of single guide RNAs (sgRNAs) that target one or more gene regulatory elements within the genome, thereby generating a plurality of test cells, wherein the one or more gene regulatory elements comprise DNAse I hypersensitivity sites, Transposase-Accessible Chromatin sites, DNA methylation, epigenetic markers, or a combination thereof, and wherein the modified target cell comprises an intracellular or cell-surface marker labelled with a fluorescently-labelled specific binding protein or at least one target gene comprising a reporter gene inserted within the coding region of the target gene; wherein the one or more gene regulatory elements comprise DNAse I hypersensitivity sites, Transposase-Accessible Chromatin sites, DNA methylation, epigenetic markers, or a combination thereof, and wherein the modified target cell comprises an intracellular or cell-surface marker labelled with a fluorescently-labelled specific binding protein or at least one target gene comprising a reporter gene inserted within the coding region of the target gene; b) isolating a population of test cells having a modulated phenotype by fluorescence-activated cell sorting or magnetic-activated cell sorting, wherein the modulated phenotype is a change in gene expression of the fluorescently-labelled specific binding protein or the reporter gene, and wherein the gene regulatory element modulates the gene expression of the at least one target gene or the intracellular marker or the cell-surface marker; c) quantitating the frequency of the sgRNAs within the population of isolated cells, wherein the sgRNAs that target one or more gene regulatory elements that modulate the phenotype are overrepresented or underrepresented in the isolated cells; and d) identifying and characterizing the sgRNAs within the population of isolated test cells thereby identifying the one or more gene regulatory elements that modulate the phenotype, wherein the modified target cell comprises a fusion protein, the fusion protein comprising a dCas9 domain and a p300 transcriptional activator domain.