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Abstract High-throughput chromosome conformation capture assays, such as Hi-C, have shown that the genome is organized into organizational units such as topologically associating domains (TADs), which can impact gene regulatory processes. The sparsity of Hi-C matrices poses a challenge for reliable detection of these units. We present GRiNCH, a constrained matrix-factorization-based approach for simultaneous smoothing and discovery of TADs from sparse contact count matrices. GRiNCH shows superior performance against seven TAD-calling methods and three smoothing methods. GRiNCH is applicable to multiple platforms including SPRITE and HiChIP and can predict novel boundary factors with potential roles in genome organization.