Methods and compositions for identifying a nucleotide sequence that encodes a polypeptide that directly or indirectly modulates the activity of a transcriptional regulatory region are provided. The methods permit the efficient screening of a large number of candidate nucleotide sequences for potential modulators of transcription. In particular, a population of polynucleotide constructs comprising a common transcriptional regulatory region operably linked to a candidate sequence is introduced into a population of host cells, and each candidate sequence is screened for modulation in its expression level, for example, using methods that employ hybridization to a complementary DNA microarray. The expression level of the candidate sequence correlates to the activity of the transcriptional regulatory region. Thus, alterations in the expression level of a candidate sequence indicate that the sequence encodes a polypeptide that modulates the activity of the transcriptional regulatory region. Compositions for practicing the invention are further provided.